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The discovery of breast cancer genes (BRCA1 and BRCA2) has led to an explosive growth in cancer screening for populations at risk. We often hear that someone has the breast cancer gene. In actuality, everyone carries these genes as part of the normal genetic makeup. Patients who are at risk for breast cancer carry mutations of these genes. The molecular diagnostic assays screen for these mutations. Although several hundred mutations have been found, these are not all of the mutations so it is possible that a patient may have a mutation of the gene which is not detected by routine screening. There is also an interesting association between some mutations and some ethnic groups. There is one mutation that is present in 20-30% of breast cancers in Ashkenazi Jews.

The following table highlights some of the salient features of these two genes.
(Adapted from Robbins Pathologic Basis of Disease 1999;1106).

Characteristic BRCA1 BRCA2
Chromosome 17q21 13q12
Gene 100 kb 70 kb
Protein 1863 amino acids 3418 amino acids
Function Tumor suppressor
Interacts with nuclear protein
Possible role in DNA repair
Tumor suppressor
Interacts with nuclear protein
Possible role in DNA repair
Mutations >500 identified >200 identified
Risk of breast CA >70% by age 80 yrs >60% by age 70 yrs
Age at onset 40-50 yrs 50 yrs and older
Risk of other tumors 30-60% of ovarian cancer by 70 yrs
Prostate and colon cancer
Male breast cancer, ovary, bladder, prostate, pancreas
Mutations in nonfamilial breast cancer <5% <5%
Epidemiology Specific mutations more common in some ethnic groups Specific mutations more common in some ethnic groups
Pathology of breast CA

Higher incidence of medullary CA (13%) and higher grade tumors
DCIS less frequent

Variable, may be mutation specific


Disease Associations  
Other Diagnostic Testing
Gross Appearance
and Clinical Variants
Histopathological Features
and Variants
Special Stains/
Electron Microscopy
Differential Diagnosis  
Commonly Used Terms  
Internet Links  

Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry.

Nanda R, Schumm LP, Cummings S, Fackenthal JD, Sveen L, Ademuyiwa F, Cobleigh M, Esserman L, Lindor NM, Neuhausen SL, Olopade OI.

Center for Clinical Cancer Genetics, Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, Ill 60637-1470, USA.

JAMA. 2005 Oct 19;294(15):1925-33. Abstract quote  

CONTEXT: Ten years after BRCA1 and BRCA2 were first identified as major breast cancer susceptibility genes, the spectrum of mutations and modifiers of risk among many ethnic minorities remain undefined.
OBJECTIVES: To characterize the clinical predictors, spectrum, and frequency of BRCA1 and BRCA2 mutations in an ethnically diverse high-risk clinic population and to evaluate the performance of the BRCAPRO statistical model in predicting the likelihood of a mutation.

DESIGN, SETTING, AND PARTICIPANTS: Comparative analysis of families (white, Ashkenazi Jewish, African American, Hispanic, Asian) with 2 or more cases of breast and/or ovarian cancer among first- and second-degree relatives. Families were identified at US sites between February 1992 and May 2003; in each family, the individual with the highest probability of being a mutation carrier was tested.

MAIN OUTCOME MEASURES: Frequency of BRCA1 and BRCA2 mutations and area under the receiver operating characteristic curve for the BRCAPRO model.

RESULTS: The mutation spectrum was vastly different between families of African and European ancestry. Compared with non-Hispanic, non-Jewish whites, African Americans had a lower rate of deleterious BRCA1 and BRCA2 mutations but a higher rate of sequence variations (27.9% vs 46.2% and 44.2% vs 11.5%; P<.001 for overall comparison). Deleterious mutations in BRCA1 and BRCA2 were highest for Ashkenazi Jewish families (69.0%). Early age at diagnosis of breast cancer and number of first- and second-degree relatives with breast and ovarian cancer were significantly associated with an increased likelihood of carrying a BRCA1 or BRCA2 mutation. In discriminating between mutation carriers, BRCAPRO performed as well in African American families as it did in white and Jewish families, with an area under the curve of 0.77 (95% confidence interval, 0.61-0.88) for African American families and 0.70 (95% confidence interval, 0.60-0.79) for white and Jewish families combined.

CONCLUSIONS: These data support the use of BRCAPRO and genetic testing for BRCA1 and BRCA2 mutations in the management of high-risk African American families. Irrespective of ancestry, early age at diagnosis and a family history of breast and ovarian cancer are the most powerful predictors of mutation status and should be used to guide clinical decision making.
Racial differences in the use of BRCA1/2 testing among women with a family history of breast or ovarian cancer.

Armstrong K, Micco E, Carney A, Stopfer J, Putt M.

Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pa, USA.
JAMA. 2005 Apr 13;293(14):1729-36. Abstract quote  

CONTEXT: Given the current context of racial disparities in health and health care and the historical context of eugenics, racial disparities in the use of genetic susceptibility testing have been widely anticipated. However, to our knowledge there are no published studies examining the magnitude and determinants of racial differences in the use of genetic susceptibility testing.

OBJECTIVES: To investigate the relationship between race and the use of BRCA1/2 counseling among women with a family history of breast or ovarian cancer and to determine the contribution of socioeconomic characteristics, cancer risk perception and worry, attitudes about genetic testing, and interactions with primary care physicians to racial differences in utilization.

DESIGN, SETTING, AND PARTICIPANTS: Case-control study (December 1999-August 2003) of 408 women with a family history of breast or ovarian cancer, of whom 217 underwent genetic counseling for BRCA1/2 testing (cases) and 191 women did not (controls). Participants received primary care within a large health system in greater Philadelphia, Pa.

MAIN OUTCOME MEASURES: Probability of carrying a BRCA1/2 mutation, socioeconomic characteristics, perception of breast and ovarian cancer risk, worry about breast and ovarian cancer, attitudes about BRCA1/2 testing, and primary care physician discussion of BRCA1/2 testing were measured prior to undergoing BRCA1/2 counseling for cases and at the time of enrollment for controls.

RESULTS: African American women with a family history of breast or ovarian cancer were significantly less likely to undergo genetic counseling for BRCA1/2 testing than were white women with a family history of breast or ovarian cancer (odds ratio, 0.22; 95% confidence interval, 0.12-0.40). This association persisted after adjustment for probability of BRCA1/2 mutation, socioeconomic characteristics, breast and ovarian cancer risk perception and worry, attitudes about the risks and benefits of BRCA1/2 testing, and primary care physician discussion of BRCA1/2 testing (adjusted odds ratio for African American vs white, 0.28; 95% confidence interval, 0.09-0.89).

CONCLUSIONS: Racial disparities in the use of BRCA1/2 counseling are large and do not appear to be explained by differences in risk factors for carrying a BRCA1/2 mutation, socioeconomic factors, risk perception, attitudes, or primary care physician recommendations. The benefit of predictive genetic testing will not be fully realized unless these disparities can be addressed.



The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.

Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892-7372, USA

N Engl J Med 1997 May 15;336(20):1401-8 Abstract quote

BACKGROUND: Carriers of germ-line mutations in BRCA1 and BRCA2 from families at high risk for cancer have been estimated to have an 85 percent risk of breast cancer. Since the combined frequency of BRCA1 and BRCA2 mutations exceeds 2 percent among Ashkenazi Jews, we were able to estimate the risk of cancer in a large group of Jewish men and women from the Washington, D.C., area.

METHODS: We collected blood samples from 5318 Jewish subjects who had filled out epidemiologic questionnaires. Carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 were identified with assays based on the polymerase chain reaction. We estimated the risks of breast and other cancers by comparing the cancer histories of relatives of carriers of the mutations and noncarriers.

RESULTS: One hundred twenty carriers of a BRCA1 or BRCA2 mutation were identified. By the age of 70, the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval, 40 to 73 percent); of ovarian cancer, 16 percent (95 percent confidence interval, 6 to 28 percent); and of prostate cancer, 16 percent (95 percent confidence interval, 4 to 30 percent). There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated.

CONCLUSIONS: Over 2 percent of Ashkenazi Jews carry mutations in BRCA1 or BRCA2 that confer increased risks of breast, ovarian, and prostate cancer. The risks of breast cancer may be overestimated, but they fall well below previous estimates based on subjects from high-risk families.

The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.

Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, Sagi M, Zlotogora J, Heching N, Peretz T.

Department of Human Genetics, Hadassah Hebrew University Hospital, Hebrew University Medical School, Jerusalem, Israel.

Am J Hum Genet 1997 Mar;60(3):505-14 Abstract quote

The mutations 185delAG, 188del11, and 5382insC in the BRCA1 gene and 6174delT in the BRCA2 gene were analyzed in 199 Ashkenazi and 44 non-Ashkenazi Jewish unrelated patients with breast and/or ovarian cancer.

Of the Jewish Ashkenazi women with ovarian cancer, 62% (13/21) had one of the target mutations, as did 30% (13/43) of women with breast cancer alone diagnosed before the age 40 years and 10% (15/141) of those with breast cancer diagnosed after the age 40 years. Age at ovarian cancer diagnosis was not associated with carrier status. Of 99 Ashkenazi patients with no family history of breast and/or ovarian cancer, 10% carried one of the mutations; in two of them the mutation was proved to be paternally transmitted. One non-Ashkenazi Jewish ovarian cancer patient from Iraq carried the 185delAG mutation.

Individual mutation frequencies among breast cancer Ashkenazi patients were 6.7% for 185delAG, 2.2% for 5382insC, and 4.5% for 6174delT, among ovarian cancer patients; 185delAG and 6174delT were about equally common (33% and 29%, respectively), but no ovarian cancer patient carried the 5382insC. More mutations responsible for inherited breast and ovarian cancer probably remain to be found in this population, since 79% of high-incidence breast cancer families and 35% of high-incidence breast/ovarian cancer families had none of the three known founder mutations.

BRCA1 and BRCA2 mutations in breast cancer families with multiple primary cancers.

Shih HA, Nathanson KL, Seal S, Collins N, Stratton MR, Rebbeck TR, Weber BL.

Department of Medicine, University of Pennsylvania, Philadelphia 19104, USA.

Clin Cancer Res 2000 Nov;6(11):4259-64 Abstract quote

Ninety-eight women ascertained from high-risk breast/ovarian cancer clinics with breast cancer reporting at least one other primary cancer in themselves or in a relative with breast cancer were compared with 99 women with breast cancer who reported a family history of breast cancer only.

All DNA was screened for coding region mutations in BRCA1 and BRCA2 using heteroduplex analysis, followed by direct sequencing. Our data indicate that 42.9% of families reporting breast and any second nonbreast type of primary cancer in the same individual had a BRCA1 or BRCA2 mutation, as compared with the 12.1% of families reporting breast cancer only (P < 0.001). Among the 66 women reporting breast cancer and a nonovarian second primary cancer, 15 (22.7%) had mutations in BRCA1 or BRCA2 (P = 0.04). Among the 32 families where ovarian cancer was the second primary cancer, 27 (84.4%) had a mutation in BRCA1 or BRCA2 (P < 0.001). BRCA1 and BRCA2 mutations were twice as common in the presence of a reported second nonovarian cancer.

These data suggest that the presence of multiple primary cancer of any kind may predict for an increased likelihood of finding a BRCA1 or BRCA2 mutation and supports previous studies suggesting that BRCA1 and BRCA2 mutations may be associated with an increased susceptibility to cancers other than breast and ovarian cancer.

Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer.

Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A.

Department of Oncology, Lund University Hospital, Sweden.

J Natl Cancer Inst 2001 Aug 15;93(16):1215-23 Abstract quote

BACKGROUND: BRCA1 and BRCA2 are the two major susceptibility genes involved in hereditary breast cancer. This study was undertaken to provide reliable population-based estimates of genetic influence and to characterize the nature and prevalence of BRCA1 and BRCA2 germline mutations in early-onset breast cancer.

METHODS: In a series comprising all women diagnosed with breast cancer under the age of 41 years in southern Sweden during 1990 through 1995 (n = 262), family history of cancer was evaluated in 95% (n = 250) of the case subjects and germline mutations in BRCA1 and BRCA2 were analyzed in 89% (n = 234). All statistical tests were two-sided.

RESULTS: A total of 97 case subjects had at least one first- or second-degree relative with breast or ovarian cancer; 34 (14%; 95% confidence interval [CI] = 9.6% to 18%) cases had at least two first- or second-degree relatives, 22 (8.8%; 95%CI = 5.3% to 12%) had one first-degree relative, and 41 (16%; 95% CI = 12% to 21%) had one second-degree relative with either cancer. If two females affected with breast or ovarian cancer who were related through an unaffected male were also defined as first-degree relatives, then a higher number of case subjects, 120 (48%; 95% CI = 42% to 54%), had at least one first-degree or second-degree relative with breast or ovarian cancer. Sixteen (6.8%; 95% CI = 4.0% to 11%) BRCA1 mutation carriers and five (2.1%; 95% CI = 0.70% to 4.9%) BRCA2 mutation carriers were identified. Among case subjects with one first- or more than one first- or second-degree relative with breast or ovarian cancer, BRCA mutations were more frequent (P<.001) than among the case subjects without this degree of family history. BRCA mutations were also statistically significantly more common among women with bilateral breast cancer than among women with unilateral breast cancer (P =.002). BRCA mutations were more common among younger case subjects than among older ones (P =.0027).

CONCLUSIONS: Almost half (48%) of women in southern Sweden with early-onset breast cancer have some family history of breast or ovarian cancer, and 9.0% of early-onset breast cancer cases are associated with a germline mutation in BRCA1 or BRCA2. Mutation carriers were more prevalent among young women, women with at least one first- or second-degree relative with breast or ovarian cancer, and women with bilateral breast cancer.

Unexpected Gynecologic Neoplasms in Patients With Proven or Suspected BRCA-1 or -2 Mutations
Implications for Gross Examination, Cytology, and Clinical Follow-up

S. Nicholas Agoff, M.D. ; Joel E. Mendelin, M.D. ; Verena S. Grieco, M.D. ; Rochelle L. Garcia, M.D.

From the Departments of Cytology (S.N.A., V.S.G.) and Pathology (S.N.A., J.E.M., R.L.G.), Harborview Medical Center/University of Washington Medical Center, Seattle, Washington, U.S.A.

Am J Surg Pathol 2002;26:171-178 Abstract quote

Identification of inheritable mutations associated with the development of malignancy has led to prophylactic surgeries to remove tissues at risk.

We report seven unrelated patients with family histories of breast and/or ovarian cancer, five of whom underwent prophylactic salpingo-oophorectomy with hysterectomy. Four had proven BRCA-1 or -2 mutations. Malignant cells were found unexpectedly in the peritoneal washings of two patients, leading to the discovery of early-stage fallopian tube carcinoma. After changing the sampling technique at our institution, two more cases of unexpected fallopian tube carcinoma in situ were discovered. Another patient had a significant family history and underwent hysterectomy for uterine fibroids, leading to the discovery of fallopian tube carcinoma. Another patient with BRCA-1 mutation had unexpected widespread primary peritoneal papillary serous adenocarcinoma. The final patient had a borderline malignant clear cell adenofibroma.

These cases underscore the importance of peritoneal cytology and thorough sampling in the management of patients undergoing hysterectomy with a family history of breast/ovarian cancer and/or known BRCA-1/BRCA-2 mutations.

As prophylactic surgeries are becoming more common secondary to advances in molecular diagnostics, pathologists need to be aware that surgical specimens from these patients may require more rigorous examination to uncover early neoplastic changes.

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications.

Honrado E, Benitez J, Palacios J.

1Human Genetics Department, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain.

Mod Pathol. 2005 Oct;18(10):1305-20. Abstract quote  

Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics.

Most BRCA1 carcinomas have the basal cell phenotype, a subtype of high-grade, highly proliferating, estrogen receptor- and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor- and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas.

Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes.

The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma.

Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases.

Breast Cancer Linkage Consortium.

Lancet 1997 May 24;349(9064):1505-10 Abstract quote

BACKGROUND: A few breast cancer cases are attributable to a hereditary predisposition to the disease. We aimed to compare the histological features of breast cancer in women carrying mutations in the susceptibility genes BRCA1 and BRCA2 with controls unselected for family history.

METHODS: The morphological characteristics of specimens from 440 patients with familial breast cancer, including 118 in carriers of BRCA1 mutations and 78 in carriers of BRCA2 mutations, were compared with those from 547 age-matched controls, unselected for family history, by seven pathologists.

FINDINGS: Cancers in carriers of BRCA1 (p < 0.0001) and BRCA2 mutations (p = 0.04) were, on average, of a higher overall grade than in controls. For example, the proportions in grade 3 were 66% of 139, 41% of 58 and 36% of 368 specimens, respectively. However, when the three grade indices were considered independently, breast cancers in BRCA1-mutation carriers showed more pleomorphism (p = 0.006), a higher mitotic count (p < 0.0001), and less tubule formation than controls (p = 0.006), whereas cancers in BRCA2-mutation carriers showed less tubule formation (p = 0.003), but no difference in pleomorphism or mitotic count. The occurrence of invasive lobular carcinoma and invasive ductal carcinoma was not significantly different between carriers of BRCA1 or BRCA2 mutations and controls. Medullary or atypical medullary carcinoma was, however, found more often in BRCA1 (13%, p < 0.0001) than in BRCA2-mutation carriers (3%) or controls (2%). Tubular carcinoma was less common in BRCA2-mutation carriers. The few mucoid carcinomas were all in familial cases. Carriers of BRCA1 mutations showed less ductal carcinoma in situ around the invasive lesion than controls (41 vs 56%, p = 0.001). Lobular carcinoma in situ was less common in familial cancers (p = 0.013), but differences were not significant for BRCA1-mutations or BRCA2-mutation carriers, separately.

INTERPRETATION: The histology of breast cancers in predisposed women differs from that in sporadic cases, and there are differences between breast cancers in carriers of BRCA1 and BRCA2 mutations. The findings suggest that breast cancer due to BRCA1, has a different natural history to BRCA2 or apparently sporadic disease, which may have implications for screening and management.

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families.

The Breast Cancer Linkage Consortium. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M, et al.

Section of Epidemiology, Institute of Cancer Research, Sutton, United Kingdom.

Am J Hum Genet 1998 Mar;62(3):676-89 Abstract quote

The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families, each with at least four cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers.

Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16% (95% confidence interval [CI] 6%-28%), suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority of families with male and female breast cancer were due to BRCA2 (76%). The largest proportion (67%) of families due to other genes was found in families with four or five cases of female breast cancer only. These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63% (95% CI 51%-77%). The estimated sensitivity was identical for direct sequencing and other techniques. The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2-mutation families, over all possible penetrance functions. The estimated cumulative risk of breast cancer reached 28% (95% CI 9%-44%) by age 50 years and 84% (95% CI 43%-95%) by age 70 years. The corresponding ovarian cancer risks were 0.4% (95% CI 0%-1%) by age 50 years and 27% (95% CI 0%-47%) by age 70 years.

The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers, but there was some suggestion of a lower risk in BRCA2 carriers <50 years of age.

Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.

Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton DF, Evans C, Deacon J, Stratton MR.

Section of Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.

J Natl Cancer Inst 1999 Jun 2;91(11):943-9 Abstract quote

BACKGROUND: Mutations in the BRCA1 and BRCA2 genes are found in most families with cases of both breast and ovarian cancer or with many cases of early-onset breast cancer. However, in an outbred population, the prevalence of BRCA1 and BRCA2 mutations in patients with breast cancer who were unselected for a family history of this disease has not been determined.

METHODS: Mutations in the BRCA1 and BRCA2 genes were detected in blood samples from two population-based series of young patients with breast cancer from Britain.

RESULTS: Mutations were detected in 15 (5.9%) of 254 women diagnosed with breast cancer before age 36 years (nine [3.5%] in BRCA1 and six [2.4%] in BRCA2) and in 15 (4.1%) of 363 women diagnosed from ages 36 through 45 years (seven [1.9%] in BRCA1 and eight [2.2%] in BRCA2). Eleven percent (six of 55) of patients with a first-degree relative who developed ovarian cancer or breast cancer by age 60 years were mutation carriers, compared with 45% (five of 11) of patients with two or more affected first- or second-degree relatives. The standardized incidence ratio for breast cancer in mothers and sisters was 365 (five observed and 1.37 expected) for 30 mutation carriers and 199 (64 observed and 32.13 expected) for 587 noncarriers. If we assume recent penetrance estimates, the respective proportions of BRCA1 and BRCA2 mutation carriers are 3.1% and 3.0%, respectively, of patients with breast cancer who are younger than age 50 years, 0.49% and 0.84% of patients with breast cancer who are age 50 years or older, and 0.11% and 0.12% of women in the general population.

CONCLUSIONS: Mutations in the BRCA1 and BRCA2 genes make approximately equal contributions to early-onset breast cancer in Britain and account for a small proportion of the familial risk of breast cancer.

Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer.

Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J, Paterson C, Ozcelik H, Goss P, Allingham-Hawkins D, Hamel N, Di Prospero L, Contiga V, Serruya C, Klein M, Moslehi R, Honeyford J, Liede A, Glendon G, Brunet JS, Narod S.

Division of Medical Oncology, Toronto-Sunnybrook Regional Cancer Centre, Toronto, ON, Canada.

J Natl Cancer Inst 1999 Jul 21;91(14):1241-7 Abstract quote

BACKGROUND: Approximately 2.0%-2.5% of Ashkenazi Jewish women carry one of three founding mutations in the BRCA1 and BRCA2 genes, and each mutation is associated with a high lifetime risk of invasive breast cancer. We investigated the extent to which these three mutations contribute to breast cancer incidence in the Ashkenazi Jewish population.

METHODS: We ascertained 457 Jewish women with prevalent cases of breast cancer who were unselected for age or family history of the disease; 412 of these women were tested for the three founder mutations (case patients). Control subjects consisted of 360 non-Jewish women with breast cancer (control patients) and 380 healthy Jewish women with no history of cancer (control subjects).

RESULTS: Mutations were found in 48 (11.7%) of 412 Jewish case patients. Forty-six of 48 mutations occurred in women with early-onset breast cancer (<50 years) or a history of ovarian or early-onset breast cancer in a first-, second-, or third-degree relative. The estimated penetrance to age 70 years for breast cancer was 59.9% for the BRCA1 gene mutations and 28.3% for the BRCA2 gene mutation. Compared with Jewish control subjects, the relative risk (RR) of breast cancer for first-degree relatives of mutation carriers was 5.16 (95% confidence interval [CI] = 3.14-8. 48), but risk was also increased for relatives of noncarriers (RR = 1.66; 95% CI = 1.18-2.33). The RR of prostate cancer for first-degree relatives of Jewish case patients was 3.36 (95% CI = 1. 49-7.56).

CONCLUSIONS: Approximately 12% of breast cancers in the Ashkenazi Jewish population are attributable to mutations in the BRCA1 or BRCA2 gene. Genetic testing may be useful when Jewish women with breast cancer are diagnosed before age 50 years or have a close relative with ovarian or early-onset breast cancer. An association between breast and prostate cancers was observed in our study population.

Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases.

Anglian Breast Cancer Study Group

Br J Cancer 2000 Nov;83(10):1301-8 Abstract quote

Estimates of the contribution of BRCA1 and BRCA2 to breast cancer incidence in outbred populations have been based on studies that are either small or have selected for cases diagnosed at an early age. Only one of these has reported an estimate of the breast cancer risk associated with a mutation in these genes, and there is no published ovarian cancer risk estimate derived from a population-based case series.

We screened a population-based series of breast cancer cases diagnosed before the age of 55 for mutations in BRCA1 and BRCA2. Pedigree information from the mutation carriers was used to estimate penetrance and the proportion of familial risk of breast cancer due to BRCA1 and BRCA2. We identified eight (0.7%) BRCA1 and 16 (1.3%) BRCA2 mutation carriers in 1220 breast cancer cases (actual sample size 1435 adjusted for 15% polymerase chain reaction failure rate). Mutation prevalence was substantially higher in cases diagnosed before 35 years-of-age and with increasing number of relatives affected with breast or ovarian cancer. However, most mutation carriers were diagnosed in the older age groups, and a minority reported a first-degree relative with breast cancer. Breast cancer penetrance by age 80 was estimated to be 48% (95% CI 7-82%) for BRCA1 mutation carriers and 74% (7-94%) for BRCA2 mutation carriers. Ovarian cancer penetrance for BRCA1 and BRCA2 combined was 22% (6-65%) by age 80. 17% of the familial risk of breast cancer was attributable to BRCA1 and BRCA2. At birth, the estimated prevalence of BRCA1 mutation carriers was 0.07% or 0.09% depending on the penetrance function used for the calculation. For BRCA2, the birth prevalence estimates were 0.14% and 0.22%.

Mutations in the genes BRCA1 and BRCA2 are rare in the population and account for a small fraction of all breast cancer in the UK. They account for less than one fifth of the familial risk of breast cancer. Eligibility criteria for BRCA1 and BRCA2 mutation testing based on family history and age of onset will identify only a small proportion of mutation carriers.

The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.

Satagopan JM, Offit K, Foulkes W, Robson ME, Wacholder S, Eng CM, Karp SE, Begg CB.

Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Cancer Epidemiol Biomarkers Prev 2001 May;10(5):467-73 Abstract quote

Several studies using families with multiple occurrences of breast cancer have provided evidence for a very high lifetime penetrance in carriers of BRCA1 or BRCA2 mutations. However, there are reasons to suspect that the estimates of penetrance from studies of cancer families may be inflated. Access to the genotypes of incident cases of breast cancer in three hospitals and from a large series of unaffected survey participants provided the basis for direct estimation of the age-specific relative risks attributable to these mutations, and the resulting lifetime penetrance, without any reference to familial aggregation of cancer.

Cases were identified from incident series of Jewish patients treated for primary breast cancer at the three hospitals. Control data were obtained from the large series of Jewish women recruited in the Washington, D.C., area by investigators at the National Cancer Institute and limited to 3434 women with no previous history of breast or ovarian cancer. All subjects were genotyped for the three mutations that are relatively common in Ashkenazi Jews, namely 185delAG and 5382 insC in BRCA1 and 6174delT in BRCA2. For BRCA1, the relative risks of breast cancer were estimated to be 21.6 in women under 40 years of age, 9.6 in women 40-49 years of age, and 7.6 in women > or = 50 years of age. On the basis of these estimates, the penetrance of breast cancer at age 70 among BRCA1 mutation carriers is estimated to be 46% (95% confidence, 31%-80%) rising to 59% (95% confidence, 40%-93%) at age 80. For BRCA2, the relative risks in the same three age categories were estimated to be 3.3, 3.3, and 4.6, respectively, resulting in a penetrance at age 70 of 26% (95% confidence, 14%-50%) rising to 38% (95% confidence, 20%-68%) at age 80.

The lifetime risk of breast cancer in Jewish women who are mutation carriers estimated via this approach is substantially lower than the reported lifetime risks estimated using multiple-case families. The risks appear to be different for carriers of BRCA1 and BRCA2 mutations.

Gene-expression profiles in hereditary breast cancer.

Hedenfalk I, Duggan D, Chen Y, Radmacher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Kallioniemi OP, Wilfond B, Borg A, Trent J.

Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4470, USA.

N Engl J Med 2001 Feb 22;344(8):539-48 Abstract quote

BACKGROUND: Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles.

METHODS: RNA from samples of primary tumor from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype.

RESULTS: Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each other. An analysis of variance between the levels of gene expression and the genotype of the samples identified 176 genes that were differentially expressed in tumors with BRCA1 mutations and tumors with BRCA2 mutations. Given the known properties of some of the genes in this panel, our findings indicate that there are functional differences between breast tumors with BRCA1 mutations and those with BRCA2 mutations.

CONCLUSIONS: Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Our results suggest that a heritable mutation influences the gene-expression profile of the cancer.


Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.

Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA.

Yale University School of Medicine, Department of Epidemiology and Public Health, New Haven, CT, 06520, USA.

Am J Hum Genet 2001 Mar;68(3):700-10 Abstract quote

A population-based series of 649 unselected incident cases of ovarian cancer diagnosed in Ontario, Canada, during 1995-96 was screened for germline mutations in BRCA1 and BRCA2.

We specifically tested for 11 of the most commonly reported mutations in the two genes. Then, cases were assessed with the protein-truncation test (PTT) for exon 11 of BRCA1, with denaturing gradient gel electrophoresis for the remainder of BRCA1, and with PTT for exons 10 and 11 of BRCA2. No mutations were found in all 134 women with tumors of borderline histology. Among the 515 women with invasive cancers, we identified 60 mutations, 39 in BRCA1 and 21 in BRCA2. The total mutation frequency among women with invasive cancers, 11.7% (95% confidence interval [95%CI] 9.2%-14.8%), is higher than previous estimates. Hereditary ovarian cancers diagnosed at age <50 years were mostly (83%) due to BRCA1, whereas the majority (60%) of those diagnosed at age >60 years were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives.

Risks of ovarian, breast, and stomach cancers and leukemias/lymphomas were increased nine-, five-, six- and threefold, respectively, among first-degree relatives of cases carrying BRCA1 mutations, compared with relatives of noncarriers, and risk of colorectal cancer was increased threefold for relatives of cases carrying BRCA2 mutations. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast-cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5' fifth, but 8.8-fold increased risk for mutations in the 3' fifth (95%CI 3.6-22.0), corresponding to a carrier penetrance of essentially 100%. Ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer-cluster region (OCCR) of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR.

For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. Past studies may have underestimated the contribution of BRCA2 to ovarian cancer, because mutations in this gene cause predominantly late-onset cancer, and previous work has focused more on early-onset disease. If confirmed in future studies, the trend in breast-cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have significant impact on treatment decisions for carriers of BRCA1-mutations. As well, BRCA2 mutations may prove to be a greater cause of cancer in male carriers than previously has been thought.


BRCA1 and prostate cancer.

Rosen EM, Fan S, Goldberg ID.

Department of Radiation Oncology, Long Island Jewish Medical Center, Long Island Campus, Albert Einstein College of Medicine, 270-05 76th Avenue, New Hyde Park, NY 11040, USA.

Cancer Invest 2001;19(4):396-412 Abstract quote

The breast cancer susceptibility gene BRCA1 on chromosome 17q21 encodes an 1863 amino acid protein that is important for normal embryonic development. Germline mutations of this gene are linked to a significantly increased lifetime risk for breast and/or ovarian cancer, and recent studies suggest that the same may be true for prostate cancer.

Several activities that may contribute to the tumor suppressor function of BRCA1 have been identified via in vitro and experimental animal studies. These include (i) regulation of cell proliferation; (ii) participation in DNA repair/recombination processes related to the maintenance of genomic integrity; (iii) induction of apoptosis in damaged cells; and (iv) regulation of transcription.

A second breast cancer susceptibility gene (BRCA2) operates in some of the same molecular pathways as BRCA1, and mutations of this gene predispose to breast and ovarian cancer and probably to other tumor types, including prostate cancer.

Finally, recent studies from our laboratory suggest that BRCA1 modulates proliferation, chemosensitivity, repair of DNA strand breaks, apoptosis induction, and expression of certain key cellular regulatory proteins (including BRCA2 and p300) in human prostate cancer cells. These activities are consistent with a putative prostate tumor suppressor function of BRCA1.



A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers.

Levy-Lahad E, Lahad A, Eisenberg S, Dagan E, Paperna T, Kasinetz L, Catane R, Kaufman B, Beller U, Renbaum P, Gershoni-Baruch R.

Medical Genetics Unit, Shaare Zedek Medical Center and Hebrew University/Hadassah Medical School, P.O. Box 3235, Jerusalem 91031, Israel.

Proc Natl Acad Sci U S A 2001 Mar 13;98(6):3232-6 Abstract quote

BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5' untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers.

To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6-9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk.

These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages.

A Single Nucleotide Polymorphism in the 5' Untranslated Region of RAD51 and Risk of Cancer among BRCA1/2 Mutation Carriers.

Wang WW, Spurdle AB, Kolachana P, Bove B, Modan B, Ebbers SM, Suthers G, Tucker MA, Kaufman DJ, Doody MM, Tarone RE, Daly M, Levavi H, Pierce H, Chetrit A, Yechezkel GH, Chenevix-Trench G, Offit K, Godwin AK, Struewing JP.

Laboratory of Population Genetics [W. W., S. M. E., D. J. K., J. P. S.], Genetic Epidemiology Branch [M. A. T.], Radiation Epidemiology Branch [M. M. D.], and Biostatistics Branch [R. E. T.], National Cancer Institute, NIH, Bethesda, Maryland 20892

Cancer Epidemiol Biomarkers Prev 2001 Sep;10(9):955-60 Abstract quote

RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers.

We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations.

We discovered two single nucleotide polymorphisms (SNPs) at positions 135 g-->c and 172 g-->t of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 g-->c, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 g-->c with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4-40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 g-->c SNP. Analysis of the RAD51:135 g-->c SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele.

We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown.




BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing.

Shattuck-Eidens D, Oliphant A, McClure M, McBride C, Gupte J, Rubano T, Pruss D, Tavtigian SV, Teng DH, Adey N, Staebell M, Gumpper K, Lundstrom R, Hulick M, Kelly M, Holmen J, Lingenfelter B, Manley S, Fujimura F, Luce M, Ward B, Cannon-Albright L, Steele L, Offit K, Thomas A, et al.

Myriad Genetics, Inc, Salt Lake City, Utah, USA

JAMA 1997 Oct 15;278(15):1242-50 Abstract quote

CONTEXT: A mutation in the BRCA1 gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete.

OBJECTIVES: To identify BRCA1 mutations and to determine factors that best predict presence of a deleterious BRCA1 mutation in patients with breast and/or ovarian cancer.

DESIGN: A complete sequence analysis of the BRCA1 coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland.

PARTICIPANTS: Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of BRCA1 mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the BRCA1 locus.

MAJOR OUTCOME MEASURES: Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations.

RESULTS: In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (unilateral or bilateral breast cancer, with or without ovarian cancer), early age at diagnosis, Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious BRCA1 mutation.

CONCLUSIONS: Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious BRCA1 mutation for a wide range of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice.

Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.

Frank TS, Manley SA, Olopade OI, Cummings S, Garber JE, Bernhardt B, Antman K, Russo D, Wood ME, Mullineau L, Isaacs C, Peshkin B, Buys S, Venne V, Rowley PT, Loader S, Offit K, Robson M, Hampel H, Brener D, Winer EP, Clark S, Weber B, Strong LC, Thomas A, et al.

Myriad Genetic Laboratories, Salt Lake City, UT 84108, USA.

J Clin Oncol 1998 Jul;16(7):2417-25 Abstract quote

PURPOSE: Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer.

PATIENTS AND METHODS: A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy.

RESULTS: Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005).

CONCLUSION: Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.

Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1.

Eng C, Brody LC, Wagner TM, Devilee P, Vijg J, Szabo C, Tavtigian SV, Nathanson KL, Ostrander E, Frank TS;

Steering Committee of the Breast Cancer Information Core (BIC) Consortium. Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.

J Med Genet 2001 Dec;38(12):824-33 Abstract quote

While sequence analysis is considered by many to be the most sensitive method of detecting unknown mutations in large genes such as BRCA1, most published estimates of the prevalence of mutations in this gene have been derived from studies that have used other methods of gene analysis.

In order to determine the relative sensitivity of techniques that are widely used in research on BRCA1, a set of blinded samples containing 58 distinct mutations were analysed by four separate laboratories.

Each used one of the following methods: single strand conformational polymorphism analysis (SSCP), conformation sensitive gel electrophoresis (CSGE), two dimensional gene scanning (TDGS), and denaturing high performance liquid chromatography (DHPLC). Only the laboratory using DHPLC correctly identified each of the mutations.

The laboratory using TDGS correctly identified 91% of the mutations but produced three apparent false positive results. The laboratories using SSCP and CSGE detected abnormal migration for 72% and 76% of the mutations, respectively, but subsequently confirmed and reported only 65% and 60% of mutations, respectively.

False negatives therefore resulted not only from failure of the techniques to distinguish wild type from mutant, but also from failure to confirm the mutation by sequence analysis as well as from human errors leading to misreporting of results. These findings characterise sources of error in commonly used methods of mutation detection that should be addressed by laboratories using these methods.

Based upon sources of error identified in this comparison, it is likely that mutations in BRCA1 and BRCA2 are more prevalent than some studies have previously reported. The findings of this comparison provide a basis for interpreting studies of mutations in susceptibility genes across many inherited cancer syndromes.

Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination.

Warner E, Plewes DB, Hill KA, Causer PA, Zubovits JT, Jong RA, Cutrara MR, DeBoer G, Yaffe MJ, Messner SJ, Meschino WS, Piron CA, Narod SA.

Division of Medical Oncology, Department of Medicine, Sunnybrook and Women's College Health Sciences Centre and University of Toronto, Ontario, Canada.

JAMA. 2004 Sep 15;292(11):1317-25. Abstract quote

CONTEXT: Current recommendations for women who have a BRCA1 or BRCA2 mutation are to undergo breast surveillance from age 25 years onward with mammography annually and clinical breast examination (CBE) every 6 months; however, many tumors are detected at a relatively advanced stage. Magnetic resonance imaging (MRI) and ultrasound may improve the ability to detect breast cancer at an early stage.

OBJECTIVE: To compare the sensitivity and specificity of 4 methods of breast cancer surveillance (mammography, ultrasound, MRI, and CBE) in women with hereditary susceptibility to breast cancer due to a BRCA1 or BRCA2 mutation.

DESIGN, SETTING, AND PARTICIPANTS: A surveillance study of 236 Canadian women aged 25 to 65 years with BRCA1 or BRCA2 mutations who underwent 1 to 3 annual screening examinations, consisting of MRI, mammography, and ultrasound at a single tertiary care teaching hospital between November 3, 1997, and March 31, 2003. On the day of imaging and at 6-month intervals, CBE was performed.

MAIN OUTCOME MEASURES: Sensitivity and specificity of each of the 4 surveillance modalities, and sensitivity of all 4 screening modalities vs mammography and CBE.

RESULTS: Each imaging modality was read independently by a radiologist and scored on a 5-point Breast Imaging Reporting and Data System scale. All lesions with a score of 4 or 5 (suspicious or highly suspicious for malignancy) were biopsied. There were 22 cancers detected (16 invasive and 6 ductal carcinoma in situ). Of these, 17 (77%) were detected by MRI vs 8 (36%) by mammography, 7 (33%) by ultrasound, and 2 (9.1%) by CBE. The sensitivity and specificity (based on biopsy rates) were 77% and 95.4% for MRI, 36% and 99.8% for mammography, 33% and 96% for ultrasound, and 9.1% and 99.3% for CBE, respectively. There was 1 interval cancer. All 4 screening modalities combined had a sensitivity of 95% vs 45% for mammography and CBE combined.

CONCLUSIONS: In BRCA1 and BRCA2 mutation carriers, MRI is more sensitive for detecting breast cancers than mammography, ultrasound, or CBE alone. Whether surveillance regimens that include MRI will reduce mortality from breast cancer in high-risk women requires further investigation.


BRCA2 Mutation-associated Breast Cancers Exhibit a Distinguishing Phenotype Based on Morphology and Molecular Profiles From Tissue Microarrays.

*Department of Pathology daggerSamuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada double daggerCoriell Institute for Medical Research, Camden, NJ section signMount Sinai Medical Center, NY parallelUniversity of Utah Health Science Center, Salt Lake City, UT paragraph signFox Chase Cancer Center, Philadelphia musical sharpUniversity of Melbourne, Melbourne, Australia **Columbia University, New York daggerdaggerNorthern California Cancer Center, Fremont double daggerdouble daggerStanford University School of Medicine, Stanford, CA section sign section signDana-Farber Cancer Institute, Boston, MA.

Am J Surg Pathol. 2007 Jan;31(1):121-128. Abstract quote

A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain.

To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry.

We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors.

We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.

Morphology of Breast Cancer as a Means of Triage of Patients for BRCA1 Genetic Testing.

*Division of Tissue Pathology, Institute of Medical and Veterinary Science, Adelaide, SA daggerTranslational Oncology, Sydney West Area Health Service, University of Sydney, Westmead Institute for Cancer Research, Westmead Millennium Institute Westmead, NSW double daggerDepartment of Pathology, University of Queensland Medical School, Heston, Qld section signDepartment of Pathology, Peter MacCallum Cancer Institute, East Melbourne, VIC

Am J Surg Pathol. 2006 Nov;30(11):1357-1366. Abstract quote

BACKGROUND: Women who have germline mutations in the BRCA1 gene are at substantially increased lifetime risk of developing breast and ovarian cancer but are otherwise normal. Currently, early age of onset of cancer and a strong family history are relied upon as the chief clues as to who should be offered genetic testing. Certain morphologic and immunohistochemical features are overrepresented in BRCA1-associated breast cancers but these differences have not been incorporated into the current selection criteria for genetic testing.

DESIGN: Each of the 4 pathologists studied 30 known cases of BRCA1- and BRCA2-associated breast cancer from kConFab families. After reviewing the literature, we agreed on a semiquantitative scoring system for estimating the chances of presence of an underlying BRCA1 mutation, based on the number of the reported prototypic features present. After a time lag of 12 months, we each examined a series of 62 deidentified cases of breast cancer, inclusive of cases of BRCA1-associated breast cancer and controls. The controls included cases of BRCA2-associated breast cancer and sporadic cases.

RESULTS: Our predictions had a sensitivity of 92%, specificity of 86%, positive predictive value of 61%, and negative predictive value of 98%. For comparison the sensitivity of currently used selection criteria are in the range of 25% to 30%.

CONCLUSION: The inclusion of morphologic and immunohistochemical features of breast cancers in algorithms to predict the likelihood of presence of germline mutations in the BRCA1 gene improves the accuracy of the selection process.


Survival after breast cancer in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

Lee JS, Wacholder S, Struewing JP, McAdams M, Pee D, Brody LC, Tucker MA, Hartge P.

Howard Hughes Medical Institute, Bethesda, MD, USA.

J Natl Cancer Inst 1999 Feb 3;91(3):259-63 Abstract quote

BACKGROUND: Studies of survival following breast and ovarian cancers in BRCA1 and/or BRCA2 mutation carriers have yielded conflicting results. We undertook an analysis of a community-based study of Ashkenazi Jews to investigate the effect of three founder mutations in BRCA1 and BRCA2 on survival among patients with breast or ovarian cancer.

METHODS: We collected blood samples and questionnaire data from 5318 Ashkenazi Jewish volunteers. The blood samples were tested for 185delAG (two nucleotide deletion) and 5382insC (single nucleotide insertion) mutations in BRCA1 and the 6174delT (single nucleotide deletion) mutation in BRCA2. To estimate survival differences in the affected relatives according to their BRCA1 and/or BRCA2 mutation carrier status, we devised and applied a novel extension of the kin-cohort method.

RESULTS: Fifty mutation carriers reported that 58 of their first-degree relatives had been diagnosed with breast cancer and 10 with ovarian cancer; 907 noncarriers reported 979 first-degree relatives with breast cancer and 116 with ovarian cancer. Kaplan-Meier estimates of median survival after breast cancer were 16 years (95% confidence interval [CI] = 11-40) in the relatives of carriers and 18 years (95% CI = 15-22) in the relatives of noncarriers, a difference that was not statistically significant (two-sided P = .87). There was also no difference in survival times among the 126 first-degree relatives with ovarian cancer. We found no survival difference between patients with breast or ovarian cancer who were inferred carriers of BRCA1 and/or BRCA2 mutations and noncarriers.

CONCLUSIONS: Carriers of BRCA1 and BRCA2 mutations appeared to have neither better nor worse survival prognosis.


Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.

Meijers-Heijboer H, van Geel B, van Putten WL, Henzen-Logmans SC, Seynaeve C, Menke-Pluymers MB, Bartels CC, Verhoog LC, van den Ouweland AM, Niermeijer MF, Brekelmans CT, Klijn JG.

Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.

N Engl J Med 2001 Jul 19;345(3):159-64 Abstract quote

BACKGROUND: Women with a BRCA1 or BRCA2 mutation have a high risk of breast cancer and may choose to undergo prophylactic bilateral total mastectomy. We investigated the efficacy of this procedure in such women.

METHODS: We conducted a prospective study of 139 women with a pathogenic BRCA1 or BRCA2 mutation who were enrolled in a breast-cancer surveillance program at the Rotterdam Family Cancer Clinic. At the time of enrollment, none of the women had a history of breast cancer. Seventy-six of these women eventually underwent prophylactic mastectomy, and the other 63 remained under regular surveillance. The effect of mastectomy on the incidence of breast cancer was analyzed by the Cox proportional-hazards method in which mastectomy was modeled as a time-dependent covariate.

RESULTS: No cases of breast cancer were observed after prophylactic mastectomy after a mean (+/-SE) follow-up of 2.9+/-1.4 years, whereas eight breast cancers developed in women under regular surveillance after a mean follow-up of 3.0+/-1.5 years (P=0.003; hazard ratio, 0; 95 percent confidence interval, 0 to 0.36). The actuarial mean five-year incidence of breast cancer among all women in the surveillance group was 17+/-7 percent. On the basis of an exponential model, the yearly incidence of breast cancer in this group was 2.5 percent. The observed number of breast cancers in the surveillance group was consistent with the expected number (ratio of observed to expected cases, 1.2; 95 percent confidence interval, 0.4 to 3.7; P=0.80).

CONCLUSIONS: In women with a BRCA1 or BRCA2 mutation, prophylactic bilateral total mastectomy reduces the incidence of breast cancer at three years of follow-up.

Occult Carcinoma in Prophylactic Oophorectomy Specimens Prevalence and Association With BRCA Germline Mutation Status

Terence J. Colgan, M.D.; Joan Murphy, M.D.; David E. C. Cole, M.D., Ph.D.; Steven Narod, M.D.; Barry Rosen, M.D.

From Mount Sinai Hospital and the Department of Laboratory Medicine and Pathobiology (T.J.C.), University of Toronto; the Division of Gynecologic Oncology, University Health Network, and the Department of Obstetrics and Gynecology (J.M.), University of Toronto; the Adult Genetics Program, University Health Network, and the Department of Laboratory Medicine and Pathobiology (D.E.C.C.), University of Toronto; Breast Cancer Research, Center for Research in Women's Health (S.N.), University of Toronto, and Public Health Sciences; and the Familial Ovarian Cancer Clinic, University Health Network, (B.R.) and the Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada.

Am J Surg Pathol 2001;25:1283-1289 Abstract quote

Prophylactic oophorectomy (PO) is an option for women at increased risk for ovarian carcinoma.

In this study the value of intensive pathologic examination of PO specimens and accompanying resected tissues in the identification of occult carcinoma and any association of occult carcinoma with BRCA germline mutation status were ascertained.

Specimens from 60 consecutive PO patients, who were not suspected of having any ovarian tumor at the time of surgery, were subjected to standardized, complete pathologic examination in a prospective study over an 8-year period. Extra-ovarian tissues were examined as well, but they were not subject to the same standardized protocol. Any occult carcinoma of the ovaries or fallopian tubes was noted. The BRCA status and follow-up of patients were obtained, if available.

Fifty-five of the 60 PO specimens did not show any evidence of malignancy. Of the 32 patients in this group followed for >1 year, all are alive and well. The remaining five patients, all BRCA1 mutation positive, showed occult carcinoma of the ovaries and/or in situ or invasive carcinoma of a fallopian tube. One of these five patients has died of abdominal carcinomatosis; four continue to be well, but follow-up is <4 years in all cases.

Occult carcinoma is present in a small proportion of BRCA-positive or unknown PO patients and may be of prognostic significance. The entire ovaries and tubes from PO patients should be submitted for histologic examination to identify malignancy.

Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.

King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K, Tait J, Ford L, Dunn BK, Costantino J, Wickerham L, Wolmark N, Fisher B; National Surgical Adjuvant Breast and Bowel Project.

University of Washington, Seattle, WA 98195, USA.

JAMA 2001 Nov 14;286(18):2251-6 Abstract quote

CONTEXT: Among cancer-free women aged 35 years or older, tamoxifen reduced the incidence of estrogen receptor (ER)-positive but not ER-negative breast cancer. The effect of tamoxifen on breast cancer incidence among women at extremely high risk due to inherited BRCA1 or BRCA2 mutations is unknown.

OBJECTIVE: To evaluate the effect of tamoxifen on incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations.

DESIGN, SETTING, AND PARTICIPANTS: Genomic analysis of BRCA1 and BRCA2 for 288 women who developed breast cancer after entry into the randomized, double-blind Breast Cancer Prevention Trial of the National Surgical Adjuvant Breast and Bowel Project (between April 1, 1992, and September 30, 1999).

MAIN OUTCOME MEASURE: Among women with BRCA1 or BRCA2 mutations, incidence of breast cancer among those who were receiving tamoxifen vs incidence of breast cancer among those receiving placebo.

RESULTS: Of the 288 breast cancer cases, 19 (6.6%) inherited disease-predisposing BRCA1 or BRCA2 mutations. Of 8 patients with BRCA1 mutations, 5 received tamoxifen and 3 received placebo (risk ratio, 1.67; 95% confidence interval, 0.32-10.70). Of 11 patients with BRCA2 mutations, 3 received tamoxifen and 8 received placebo (risk ratio, 0.38; 95% confidence interval, 0.06-1.56). From 10 studies, including this one, 83% of BRCA1 breast tumors were ER-negative, whereas 76% of BRCA2 breast tumors were ER-positive.

CONCLUSION: Tamoxifen reduced breast cancer incidence among healthy BRCA2 carriers by 62%, similar to the reduction in incidence of ER-positive breast cancer among all women in the Breast Cancer Prevention Trial. In contrast, tamoxifen use beginning at age 35 years or older did not reduce breast cancer incidence among healthy women with inherited BRCA1 mutations. Whether tamoxifen use at a younger age would reduce breast cancer incidence among healthy women with BRCA1 mutations remains unknown.

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Last Updated January 24, 2007

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