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This syndrome, sometimes abbreviated HNPCC, accounts for about 5-13% of all colorectal carcinomas. The current criteria is primarily by a combination of clinical criteria.

Amsterdam Criteria Three first-degree relatives with histologically verified colorectal cancer
Two consecutive generations are affected
Age of onset <50 years for at least 1 patient
Bethesda Criteria Individuals with cancer in families that meet the Amsterdam criteria
  Individuals with 2 HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers (endometrial, ovarian, gastric, hepatobiliary, or small bowel cancer or transitional cell carcinoma of the renal pelvis or ureter)
  Individuals with colorectal cancer and a first degree relative with colorectal cancer or HNPCC-related extracolonic cancer or colorectal adenoma
One of the cancers diagnosed <45 years and adenoma diagnosed <45 years
  Individuals with colorectal cancer or endometrial cancer <45 years
  Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribriform) on histopathology diagnosed at age <45 years
  Individuals with signet-ring-cell-type colorectal cacner diagnosed <45 years (>50% signet ring cells)
  Individuals with colorectal adenomas diagnosed at age <40 years


Epidemiology Ashkenazi Jews
Disease Associations Muir-Torre syndrome
Urothelial carcinoma
Other Diagnostic Testing
Detection of mutations in mismatch repair genes
Gross Appearance
and Clinical Variants
Histopathological Features and Variants  
Special Stains/
Electron Microscopy
Differential Diagnosis  
Commonly Used Terms  
Internet Links  



Clinical characteristics and diagnosis of patients with hereditary nonpolyposis colorectal cancer.

Cai SJ, Xu Y, Cai GX, Lian P, Guan ZQ, Mo SJ, Sun MH, Cai Q, Shi DR.

Department of Abdominal Surgery, Shanghai Cancer Hospital/Institute, Fudan University, Shanghai 200032, China.

World J Gastroenterol 2003 Feb;9(2):284-7 Abstract quote

AIM: To study the clinical characteristics of hereditary nonpolyposis colorectal cancer (HNPCC) in the Chinese population and discuss the identification and management of the patients with HNPCC.

METHODS: A series of 140 patients with colorectal cancers (CRC) and HNPCC associated tumors from 30 families fulfilling the Amsterdam criteria were analyzed.

RESULTS: A total of 118 patients had CRC. Average age at diagnosis of the first CRC was 45.7 years, 56.8 % and 23.4 % of the first CRC were located proximal to the splenic flexure and in the rectum respectively. Twenty-three (19.5 %) had synchronous and metachronous CRC. Twenty-seven patients were found to have extracolonic tumors. Gastric carcinoma was the most common tumor type in our series (44.4 %).

CONCLUSION: The frequency of HNPCC was 2.6 % in our series of patients. The main features are an excess of early onset with a propensity to involve the proximal colon, and high frequency of multiple foci. Management and surveillance for these patients should be different from sporadic CRC. Contrary to American and European reports, gastric cancer seems more frequent than endometrial cancer in Chinese. It is necessary to formulate a new HNPCC criterion for Chinese patients.

After hMSH2 and hMLH1--what next? Analysis of three-generational, population-based, early-onset colorectal cancer families.

Jenkins MA, Baglietto L, Dite GS, Jolley DJ, Southey MC, Whitty J, Mead LJ, St John DJ, Macrae FA, Bishop DT, Venter DJ, Giles GG, Hopper JL.

Centre for Genetic Epidemiology, The University of Melbourne, 723 Swanston Street, Carlton Victoria 3053, Australia.

Int J Cancer 2002 Nov 10;102(2):166-71 Abstract quote

The aim of our study was to examine the role of genetic factors on early-onset colorectal cancer after excluding the impact of germline mutations in the two major mismatch repair genes. A total of 131 incident probands, under 45 years at diagnosis of a first primary colorectal cancer selected from the Victorian Cancer Registry, and their first-and second-degree relatives, were interviewed.

Germline DNA from all 12 probands with a family history meeting the modified Amsterdam Criteria for Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and a random sample of 31 of the remaining probands was screened for mutations in hMSH2 and hMLH1 via manual sequencing. Germline mutations were identified in 6 of the 131 probands (5%), all from the "HNPCC" families. Of the remaining 125 probands, 51 (41%) reported at least one first-or second-degree relative with colorectal cancer with an excess of colorectal cancer in first-degree relatives (SMR = 2.7, 95% CI = 1.7-4.1, p < 0.001). The lifetime risk to age 70 for first-degree relatives was 8.0% (5.0-12.8%), compared to the Victorian population risk of 3.2% (p = 0.01).

The best fitting major gene model was a recessively-inherited risk of 98% to age 70 (95% CI = 24-100%) carried by 0.17% of the population and would explain 15% of all colorectal cancer in cases with a diagnosis before age 45. Early-onset colorectal cancer is strongly familial even after excluding families found to be segregating a mutation in either of the 2 major mismatch repair genes. There is evidence for a role of yet to be identified genes associated with a high recessively-inherited risk of colorectal cancer.


The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population.

Foulkes WD, Thiffault I, Gruber SB, Horwitz M, Hamel N, Lee C, Shia J, Markowitz A, Figer A, Friedman E, Farber D, Greenwood CM, Bonner JD, Nafa K, Walsh T, Marcus V, Tomsho L, Gebert J, Macrae FA, Gaff CL, Paillerets BB, Gregersen PK, Weitzel JN, Gordon PH, MacNamara E, King MC, Hampel H, De La Chapelle A, Boyd J, Offit K, Rennert G, Chong G, Ellis NA.

Department of Medicine, Sir Mortimer B Davis-Jewish General Hospital, Montreal, Quebec, Canada, H3G 1A4.

Am J Hum Genet 2002 Dec;71(6):1395-412 Abstract quote

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes.

We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G-->C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis.

In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer.

When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.


Clinical phenotypes of hereditary nonpolyposis colorectal cancer in Chinese population.

Sheng J, Shen Z, Fan C.

Department of Gastroentorology, General Hospital of Beijing Military Area, Beijing 100700, China.

Zhonghua Yi Xue Za Zhi 2002 Oct 25;82(20):1371-4 Abstract quote

OBJECTIVE: To investigste the clinical phenotypes of hereditaty nonpolyposis colorectal cancer (HNPCC) in Chinese population.

METHODS: Data of 34 HNPCC families diagnosed according to Armsterdam IICriteria and Japan Criteria, including age of diagnosis, site of cancer inclusive of abenteric cancer, history of synchronous and/or metachronous colorectal cancer, histopathology of tumor, clinical manifestations, and genealogy were collected and analyzed.

RESULTS: Out of the 612 members aged over 18 of these 34 families 140 persons were diagnosed as HNPCC patients with 154 cancer foci, 93 males and 47 females. The median age of confirmed diagnosis of HNPCC was 45.3 years. 62.1% of them developed the cancer before the age of 50 and 87.1% of them developed the cancer before the age of 60. Out of the 154 primary cancer foci, 31 were extracolonic (20.1%), including synchronous and/or metachronous cancers, with gastric cancer accounting for 41.9% (13/31), and 123 were colonic cancers (79.9%). Out of the 116 cases of colorectal cancer, there were 77 cases of proximal colon cancer (66.4%) and 39 cases of distal colon cancer (33.7%). There were 11 cases of synchronous and/or metachronous cancer (7.86%). The main clinical manifestatioins included hematochezia, anemia, abdominal mass, and abdominal pain.

CONCLUSION: In comparison with the facts among Westerners, HNPCC occurred earlier; the proportions of proximal colon cancer, extracolonic cancer, and synchronous and/or metachronous cancers are larger; and gastric cancer accounts for a greater percentage among Chinese.


Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.

Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, Seminara D.

Department of Medical Genetics, Mayo Clinic, Rochester, Minn, USA.
JAMA. 2005 Apr 27;293(16):1979-85. Abstract quote  

CONTEXT: Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown.

OBJECTIVE: To determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities.

DESIGN, SETTING, AND PARTICIPANTS: Identification (1997-2001) of 161 AC-I pedigrees from multiple population- and clinic-based sources in North America and Germany, with families grouped into those with (group A) or without (group B) MMR deficiency by tumor testing. A total of 3422 relatives were included in the analyses.

MAIN OUTCOME MEASURES: Cancer incidence in groups A and B (excluding the 3 affected members used to define each pedigree as AC-I) and computed age- and sex-adjusted standardized incidence ratios (SIRs) using Surveillance, Epidemiology, and End Results data. RESULTS: Group A families from both population- and clinic-based series showed increased incidence of the HNPCC-related cancers. Group B families showed increased incidence only for colorectal cancer (SIR, 2.3; 95% confidence interval, 1.7-3.0) and to a lesser extent than group A (SIR, 6.1; 95% confidence interval, 5.2-7.2) (P<.001).

CONCLUSIONS: Families who fulfill AC-I criteria but who have no evidence of a DNA MMR defect do not share the same cancer incidence as families with HNPCC-Lynch syndrome (ie, hereditary MMR deficiency). Relatives in such families have a lower incidence of colorectal cancer than those in families with HNPCC-Lynch syndrome, and incidence may not be increased for other cancers. These families should not be described or counseled as having HNPCC-Lynch syndrome. To facilitate distinguishing these entities, the designation of "familial colorectal cancer type X" is suggested to describe this type of familial aggregation of colorectal cancer.

Microsatellite instability in benign skin lesions in hereditary non-polyposis colorectal cancer syndrome.

Swale VJ, Quinn AG, Wheeler JM, Beck NE, Dove-Edwin I, Thomas HJ, Bodmer WF, Bataille VA.

Academic Department of Dermatology, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK.

J Invest Dermatol 1999 Dec;113(6):901-5 Abstract quote

The coexistence of cutaneous and extra-cutaneous malignancies within one family could be explained by shared genetic mechanisms such as common tumor suppressor gene mutations or oncogene activation, as well as mutations in DNA repair genes. Hereditary non-polyposis colorectal cancer syndrome (HNPCC) and its variant Muir-Torre syndrome (MTS) are caused by germline DNA mismatch repair gene mutations. Colonic and endometrial tumors from HNPCC patients exhibit microsatellite instability (MSI), as do sebaceous lesions in MTS. We recruited individuals from cancer prone families to determine if MSI is found in benign and malignant skin lesions and to assess whether MSI in the skin is predictive of genomic instability with susceptibility to tumors characteristic of HNPCC.

One hundred and fifteen benign, dysplastic, and malignant skin lesions from 39 cancer prone families were analyzed. Thirteen benign skin lesions from three individuals belonging to two HNPCC pedigrees showed MSI. No mutations in hMSH2 and hMLH1 were found in two of the three individuals with RER + skin lesions. We found MSI in non-sebaceous non-dysplastic skin lesions in HNPCC pedigrees. MSI was not found in skin lesions within other family cancer syndromes.

These results have important clinical implications as the detection of MSI in prevalent readily accessible skin lesions could form the basis of noninvasive screening for HNPCC families. It may also be a valuable tool in the search for new mismatch repair genes.


Hereditary non-polyposis colorectal cancer associated with disseminated superficial porokeratosis. Microsatellite instability in skin tumours.

Takata M, Shirasaki F, Nakatani T, Takehara K.

Department of Dermatology, Kanazawa University School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan.

Br J Dermatol 2000 Oct;143(4):851-5 Abstract quote

A 73-year-old man presented with typical lesions of disseminated superficial porokeratosis (DSP) and multiple seborrhoeic keratoses on his face, trunk and extremities, and later developed a keratoacanthoma on his lip. He belonged to a cancer-prone pedigree susceptible to colonic, uterine and other internal cancers, and had a personal history of early gastric cancer and advanced adenocarcinoma of the descending colon without adenomatous polyps at age 59 years.

Polymerase chain reaction amplification of skin samples for seven separate microsatellite polymorphisms revealed microsatellite instability (MSI) at multiple loci in five of six seborrhoeic keratoses and the keratoacanthoma, strongly suggesting underlying defects in DNA mismatch repair. Although no germline mutations in two mismatch repair genes hMSH2 and hMLH1 were found, our patient was recognized as having hereditary non-polyposis colorectal cancer (HNPCC) based on the family history and the findings of the microsatellite analysis of skin tumours. This confirmed the usefulness of detection of MSI in prevalent and readily accessible skin lesions, including non-sebaceous non-dysplastic tumours such as seborrhoeic keratosis in the screening of HNPCC families.

Although DSP may also be inherited as an autosomal dominant condition, this particular skin disease appeared to be sporadic in our patient and, to our knowledge, no association of DSP or other forms of porokeratosis with HNPCC has previously been reported. In contrast to the seborrhoeic keratoses and keratoacanthoma, no MSI was observed in two samples from DSP lesional epidermis examined.


Hereditary nonpolyposis colorectal cancer syndrome in a patient with urothelial carcinoma of the upper urothelial tract.

Hartmann A, Cheville JC, Dietmaier W, Hofstadter F, Burgart LJ, Blaszyk H.

Institute of Pathology, University of Regensburg, Regensburg, Germany (Drs Hartmann, Dietmaier, Hofstadter, and Blaszyk); and the Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minn (Drs Cheville and Burgart).

Arch Pathol Lab Med 2003 Feb;127(2):E60-3 Abstract quote

Urothelial carcinoma of the upper urinary tract is relatively uncommon but may develop as a manifestation of the hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which is characterized by mutations in a number of DNA mismatch repair genes and detectable as microsatellite instability or loss of the respective protein by immunostaining.

No well-established screening test is available for urothelial carcinomas of the upper urinary tract, and little is known of the clinical impact of screening for HNPCC in patients with upper urinary tract cancer.

We describe herein a patient with a urothelial carcinoma of the ureter and a strongly positive history of cancer, who was subsequently found to have HNPCC.

Our findings reinforce the importance of obtaining a comprehensive history of cancer in patients with urothelial carcinoma of the renal pelvis and ureter. Subsequent identification of individuals with HNPCC enables the patient and at-risk relatives to benefit from targeted surveillance and management programs.


DNA mismatch repair (MMR) deficiency

Cancer Genet Cytogenet 1997;93:84-99

DNA mismatch repair system
Family of genes with homologues to bacterial MutS and MutL proteins



Germline mutations of hMSH2 and hMLH1 account for 50% of all cases of HNPCC colon cancer

MMR proteins interact as heterodimers:

hMSH2-hMSH6 have been shown to recognize DNA mismatches resulting from spontaneous errors occurring during replication

Preferred targets of spontaneous replication errors are the simple repetitive sequences (microsatellites)

A MMR deficiency results in microsatellite instability (MSI) in which the lengthy of normally stable repeats varies considerably

Cancer may result as failure to repair replication errors within repeat sequences in genes relevant for growth control and differentiation like TGFbeta, BAX, and IGFRII

  Hum Pathol 2000;31:1506-1514
High MSI correlated with:
Loss of either hMLH1 or hMSH2
Presence of bcl-2
Absence of p53

DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer.

Iino H, Simms L, Young J, Arnold J, Winship IM, Webb SI, Furlong KL, Leggett B, Jass JR.

First Department of Surgery, Yamanashi Medical University, Yamanashi, Japan.

Gut 2000 Jul;47(1):37-42 Abstract quote

BACKGROUND AND AIM: Hereditary non-polyposis colorectal cancer (HNPCC), as its name implies, is associated with few adenomas, and the early evolution of colorectal neoplasia is poorly understood. In this study our aim was to clarify the genetic profiles of benign polyps in subjects with HNPCC using a combined molecular and immunohistochemical approach.

METHODS: Thirty adenomas and 17 hyperplastic polyps were obtained from 24 affected HNPCC subjects. DNA was extracted from paraffin embedded tissue by microdissection and analysed for the presence of microsatellite instability (MSI) and mutations in five genes known to be targets in mismatch repair deficiency (TGFbetaRII, IGF2R, BAX, hMSH3, and hMSH6). Serial sections were stained by immunohistochemistry for hMLH1 and hMSH2.

RESULTS: Twenty four (80%) of 30 adenomas showed MSI. Of MSI positive adenomas, 66.7% showed MSI at more than 40% of markers (high level of MSI (MSI-H)). Two of 17 hyperplastic polyps revealed MSI at one marker (low level of MSI (MSI-L)). A significant association was found between MSI-H and high grade dysplasia in adenomas (p=0.004). Eight of nine adenomas with mutations of coding sequences revealed high grade dysplasia and all nine were MSI-H. Four of the nine ranged in size from 2 to 5 mm. The presence of the hMSH6 mutation was significantly correlated with high levels of MSI (80% of markers) (p<0.02). Twenty four adenomas gave evaluable results with immunohistochemistry. One of six (17%) microsatellite stable, six of seven (86%) MSI-L, and 11 of 11 (100%) MSI-H adenomas showed loss of either hMLH1 or hMSH2.

CONCLUSIONS: Most adenomas in subjects with a definite diagnosis of HNPCC show MSI (80%). The finding of MSI-L is usually associated with loss of expression of hMLH1 or hMSH2, unlike the situation in MSI-L sporadic colorectal cancer. The transition from MSI-L to MSI-H correlated with the finding of high grade dysplasia and mutation of coding sequences and may be driven by mutation of secondary mutators such as hMSH3 and hMSH6. Advanced genetic changes may be present in adenomas of minute size.



Antibody-based screening for hereditary nonpolyposis colorectal carcinoma compared with microsatellite analysis and sequencing.

Christensen M, Katballe N, Wikman F, Primdahl H, Sorensen FB, Laurberg S, Orntoft TF.

Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.


Cancer 2002 Dec 1;95(11):2422-30 Abstract quote

BACKGROUND: Germline mutations in the DNA mismatch repair genes, MSH2, MLH1, and others are associated with hereditary nonpolyposis colorectal cancer (HNPCC). Due to the high costs of sequencing, cheaper screening methods are needed to identify HNPCC cases. Ideally, these methods should have a high sensitivity and identify all mutated cases without too many false-positive cases.

METHODS: Sequencing was compared with microsatellite analysis and immunohistochemistry to detect the presence or absence of the mismatch repair proteins. In the current study, the authors examined 42 patients with colorectal carcinoma of whom 11 met the Amsterdam criteria and 31 were suspected to belong to HNPCC families. Thirty-five patients were examined by microsatellite analysis, 40 by immunohistochemical staining, and in 31 patients both the MLH1 and MSH2 genes were sequenced.

RESULTS: Ninety-two percent of patients with germ line mutations were detected by either immunohistochemistry or microsatellite instability, indicating that a combination of these methods may be suitable for HNPCC screening. Microsatellite instability and abnormal immunohistochemical staining were found in 73% of the tumors. Concordance among the three methods was found in 74 % of the tumors.

CONCLUSIONS: The authors suggest that immunohistochemistry should be used in combination with microsatellite analysis to prescreen suspected HNPCC patients for the selection of cases where sequencing of the MLH1 and MSH2 mismatch repair genes is indicated.

Causes of microsatellite instability in colorectal tumors: implications for hereditary non-polyposis colorectal cancer screening.

Potocnik U, Glavac D, Golouh R, Ravnik-Glavac M.

Laboratory of Molecular Genetics, Institute of Pathology, Medical Faculty, Ljubljana, Slovenia.

Cancer Genet Cytogenet 2001 Apr 15;126(2):85-96 Abstract quote

Microsatellite instability (MSI) analysis was performed using a "reference panel" of microsatellite markers in 345 unselected primary colorectal cancers (CRC). Thirty-five (10%) tumors were classified as high MSI (MSI-H).

We identified 6 (17%) MSI-H tumors with germline mutations in mismatch repair (MMR) genes (tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome) and 29 (83%) MSI-H tumors without germline MMR mutations (sporadic MSI-H tumors). Hypermethylation of the hMLH1 promoter was found in 26/29 (90%) sporadic MSI-H tumors but only in 1/6 (17%) HNPCC tumors (P .001). Somatic alterations were identified in both MMR genes in HNPCC tumors but mainly in the hMSH2 gene in sporadic MSI-H tumors. LOH at MMR loci was detected in 3/6 (50%) HNPCC tumors and in 4/26 (15%) informative sporadic MSI-H tumors. These results together indicate different mode of inactivation of MMR genes in sporadic MSI-H tumors versus MSI-H tumors in HNPCC patients.

We therefore propose that MSI analysis of newly diagnosed primary CRC followed by methylation analysis of hMLH1 promoter in MSI-H tumors and mutational analysis of MMR genes in MSI-H tumors lacking hMLH1 promoter methylation might be an efficient molecular genetic approach for HNPCC screening.

Hereditary non-polyposis colorectal cancer (HNPCC): new germline mutation (190-191 del AA) in the human MLH1 gene and review of clinical guidelines for surveillance of affected families.

Schiemann U, Papatheodorou L, Glasl S, Gross M.

Medizinische Poliklinik, Ludwig-Maximilians-Universitat Munchen, Pettenkoferstr. 8a, D-80336 Munchen, Germany.

Eur J Med Res 2001 Mar 26;6(3):93-100 Abstract quote

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common genetic diseases comprising at least 5-6% of all colorectal cancers. It is characterized by early onset and mostly right-sided tumors (proximal to the splenic flexure). Molecular analyses are useful methods for diagnosis in index patients and for the detection of risk persons in affected families.

A 37-year-old female patient whose family history fulfilled the criteria for hereditary non-polyposis colorectal cancer (HNPCC) was studied using PCR and DNA sequencing for the detection of mutations in the mismatch repair genes hMSH2 and hMLH1. Additionally, literature was reviewed (MEDLINE research until 2000) concerning clinical guidelines for surveillance in HNPCC families. A new deletion of two adenosine nucleotides (190-191 del AA) at codon 64 in exon 2 of the hMLH1 gene was found. The frameshift led to a stop codon at amino acid position 75. This mutation is considered to be disease causing in the development of the colorectal cancer of this family. Six publications with detailed recommendations for the surveillance of risk persons were found in the literature.

Following their guidelines, colonoscopy is recommended from 20-30 years on for members of a family who fulfills either the Amsterdam criteria or the Bethesda criteria in combination with a detection of microsatellite instability. Female risk persons should be investigated gynecologically, including a transvaginal ultrasound examination, from 25-35 years on for the early detection of endometrial or ovarian cancer. Recommendations for gastroscopy, abdominal ultrasound examination and urine analysis are not given in all publications. Genetic counseling is recommended from 18 years on for all members of affected families.

Detection of mutations in mismatch repair genes in Portuguese families with hereditary non-polyposis colorectal cancer (HNPCC) by a multi-method approach.

Fidalgo P, Almeida MR, West S, Gaspar C, Maia L, Wijnen J, Albuquerque C, Curtis A, Cravo M, Fodde R, Leitao CN, Burn J.

Gastroenterology Department, Instituto Portugues de Oncologia, Lisbon, Portugal.

Eur J Hum Genet 2000 Jan;8(1):49-53 Abstract quote

Mutation searching was performed in the hMSH2 and hMLH1 genes in 20 Portuguese families representing 124 registered affected individuals. Of the 20, 16 fulfilled the classic 'Amsterdam' criteria for HNPCC, whereas the remaining four families satisfied a modified set of criteria. These criteria required a CRC diagnosed before age 50 years and cancers diagnosed in two other relatives within the HNPCC spectrum.

A multi-method approach was performed using the protein truncation test (PTT), single strand conformation polymorphism (SSCP) with two different sets of conditions, heteroduplex analysis (HA) and denaturing gradient gel electrophoresis (DGGE). Putative phenotype-genotype correlations were also explored. Ten different germline mutations were identified. Six of these were found in hMLH1 in seven families and four in hMSH2 in four families. SSCP and DGGE had the highest diagnostic yields with the percentage of variants detected above 67% and together HA and PTT had the lowest. No single technique detected all variants. Trends for the absence of extracolonic manifestations were observed in families carrying hMLH1 germline mutations (four of seven in hMLH1 vs one of four in hMSH2). Most of the families with rectal cancer were associated with hMLH1 (six of seven in hMLH1 vs two of four in hMSH2).

A multi-technique approach is necessary to identify a high percentage of germline mutations. Seven novel mutations were found in this Portuguese population.

Microsatellite instability in colorectal-cancer patients with suspected genetic predisposition.

Calistri D, Presciuttini S, Buonsanti G, Radice P, Gazzoli I, Pensotti V, Sala P, Eboli M, Andreola S, Russo A, Pierotti M, Bertario L, Ranzani GN.

Dipartimento di Genetica e Microbiologia, University of Pavia, Italy.

Int J Cancer 2000 Jan 20;89(1):87-91 Abstract quote

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome linked to DNA-mismatch-repair (MMR) gene defects, which also account for microsatellite instability (MSI) in tumour tissues. Diagnosis is based mainly on family history, according to widely accepted criteria (Amsterdam Criteria: AC).

Aim of this work was to assess MSI in colorectal-cancer patients with suspected genetic predisposition, and to verify whether MSI represents a tool to manage MMR gene (hMSH2 and hMLH1) mutation analysis. We investigated 13 microsatellites (including the 5 NCI/ICG-HNPCC markers) in 45 patients with suspected hereditary predisposition (including 16 subjects from HNPCC families fulfilling the AC). We found MSI-H (high frequency of instability, i.e., in > or =30% of the markers) in 85% of the HNPCC patients and in 16% of the non-HNPCC subjects. The 5 NCI/ICG-HNPCC microsatellites proved to be the most effective in detecting MSI, being mononucleotide repeats the most unstable markers. We investigated the association between hMSH2- and hMLH1 gene mutations and MSI.

Our results indicate that AC are highly predictive both of tumour instability and of MMR-gene mutations. Therefore, as the most likely mutation carriers, HNPCC subjects might be directly analyzed for gene mutations, while to test for MSI in selected non-HNPCC patients and to further investigate MMR genes in MSI-H cases, appears to be a cost-effective way to identify subjects, other than those from kindred fulfilling AC, who might benefit from genetic testing.

Extensive molecular screening for hereditary non-polyposis colorectal cancer.

Dieumegard B, Grandjouan S, Sabourin JC, Le Bihan ML, Lefrere I, Bellefqih, Pignon JP, Rougier P, Lasser P, Benard J, Couturier D, Bressac-de Paillerets B.

Unite des Marqueurs Genetiques des Cancers, Institut Gustave Roussy, Villejuif, France.

Br J Cancer 2000 Feb;82(4):871-80 Abstract quote

The genetic abnormalities underlying hereditary non-polyposis colorectal cancer (HNPCC) are germline mutations in one of five DNA mismatch repair genes or in the TGFbetaRII gene.

The aim of our study was to evaluate the significance of simple tests performed on tumours to select appropriate candidates for germline mutational analysis. We studied three groups of patients, HNPCC kindreds fulfilling the International Collaborative Group (ICG) criteria (n = 10), families in which at least one of the criteria was not satisfied (n = 7) and sporadic colorectal cancer (CRC) diagnosed before the age of 50 (n = 17). We searched for microsatellite instability (MSI), presence of hMSH2 and hMLH1 germline mutations, expression of hMSH2, hMLH1 and p53 proteins in tumoural tissue samples by immunostaining. Fifteen out of 17 (88%) of HNPCC and incomplete HNPCC cases were MSI and eight pathogenic germline mutations in hMSH2 or hMLH1 were detected in these two groups (53%). All the 17 early-onset sporadic cases were MSS and no germline mutations were detected among the seven investigated cases. Thirteen out of 15 (81%) familial cases were MSI and p53 protein-negative, whereas 13/14 (93%) sporadic cases were MSS and strongly p53 protein-positive.

This extensive molecular investigation shows that simple tests such as MS study combined with hMSH2 and hMLH1 protein immunostaining performed on tumoural tissues may provide valuable information to distinguish between familial, and probably hereditary, and sporadic CRC cases.

Value of pedigree/clinical data, immunohistochemistry and microsatellite instability analyses in reducing the cost of determining hMLH1 and hMSH2 gene mutations in patients with colorectal cancer.

Debniak T, Kurzawski G, Gorski B, Kladny J, Domagala W, Lubinski J.

Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.

Eur J Cancer 2000 Jan;36(1):49-54 Abstract quote

The aim of this study was to evaluate the significance of pedigree/clinical data, immunohistochemistry (IHC) and microsatellite instability (MI) analyses in the reduction of costs of constitutional hMLH1 and hMSH2 gene mutation diagnosis in patients with colorectal cancers (CRC). P

edigree/clinical data were evaluated on a series of 168 patients with CRC, including 43 consecutive sporadic late-onset and 25 consecutive, definitive or suspected hereditary non-polyposis colorectal cancer (HNPCC) cases, examined by IHC and MI analyses. In the latter group, 6/25 (24%) constitutional mutations were found. We detected no germline mutations in the sporadic late-onset patients. The lowest costs (880 Euro/mutation detected) were achieved by performing pedigree/clinical data (for exclusion of late-onset sporadic CRC) in conjuction with IHC only.

In this model 1/6 (17%) mutations was missed. Additional preselection by IHC and MI analyses before sequencing was required to detect all mutations. In this approach, which seems to be the most effective in the search for hMLH1 and hMSH2 gene mutation, the cost was 1767 euro/mutation detected.

High throughput genetic screening for the detection of hereditary non-polyposis colon cancer (HNPCC) using capillary electrophoresis.

Merkelbach-Bruse S, Kose S, Losen I, Bosserhoff AK, Buettner R.

Institute of Pathology, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-5207 Aachen, Germany.

Comb Chem High Throughput Screen 2000 Dec;3(6):519-24 Abstract quote

Approximately 5-10% of all colorectal carcinomas arise from cancer predisposition syndromes caused by heterozygote germline mutations in post-replicative DNA mismatch repair (MMR) genes. In contrast to gastrointestinal polyposis syndromes, carcinomas in these patients do not occur on the background of increased numbers of polyps and hence are refered to as hereditary non-polyposis colorectal cancers (HNPCC). Six different MMR genes, MSH2, MSH3, MSH6, MLH1, MLH3 and PMS2, have been identified in the human genome. In the majority of HNPCC patients, heterozygote germline mutations are present in the MSH2 or MLH1 gene. Detection of mutations by conventional sequencing technology is expensive and labor intensive due to the complex intron and/or exon structures.

In this study, we therefore have explored whether capillary electrophoresis-based single strand conformation polymorphism (SSCP-CE) provides a reliable means for mutation screening.

We have tested different MLH1 mutations in exons 9 and 16 and find that SSCP-CE produces reliable electrophoretic patterns that allow recognition of wild-type alleles, microdeletions and point mutations.

In summary, SSCP-CE provides a rapid, automated, and cost-effective technology for MSH2 and MLH1 mutation screening and will facilitate genetic diagnostics for HNPCC patients.



Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1.

Syngal S, Fox EA, Eng C, Kolodner RD, Garber JE.

Division of Gastroenterology, Dana-Farber Cancer Institute, and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA.

J Med Genet 2000 Sep;37(9):641-5 Abstract quote

BACKGROUND AND AIMS: There are multiple criteria for the clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC). The value of several of the newer proposed diagnostic criteria in identifying subjects with mutations in HNPCC associated mismatch repair genes has not been evaluated, and the performance of the different criteria have not been formally compared with one another.

METHODS: We classified 70 families with suspected hereditary colorectal cancer (excluding familial adenomatous polyposis) by several existing clinical criteria for HNPCC, including the Amsterdam criteria, the Modified Amsterdam criteria, the Amsterdam II criteria, and the Bethesda criteria. The results of analysis of the mismatch repair genes MSH2 and MLH1 by full gene sequencing were available for a proband with colorectal neoplasia in each family. The sensitivity and specificity of each of the clinical criteria for the presence of MSH2 and MLH1 mutations were calculated.

RESULTS: Of the 70 families, 28 families fulfilled the Amsterdam criteria, 39 fulfilled the Modified Amsterdam Criteria, 34 fulfilled the Amsterdam II criteria, and 56 fulfilled at least one of the seven Bethesda Guidelines for the identification of HNPCC patients. The sensitivity and specificity of the Amsterdam criteria were 61% (95% CI 43-79) and 67% (95% CI 50-85). The sensitivity of the Modified Amsterdam and Amsterdam II criteria were 72% (95% CI 58-86) and 78% (95% CI 64-92), respectively. Overall, the most sensitive criteria for identifying families with pathogenic mutations were the Bethesda criteria, with a sensitivity of 94% (95% CI 88-100); the specificity of these criteria was 25% (95% CI 14-36). Use of the first three criteria of the Bethesda guidelines only was associated with a sensitivity of 94% and a specificity of 49% (95% CI 34-64).

CONCLUSIONS: The Amsterdam criteria for HNPCC are neither sufficiently sensitive nor specific for use as a sole criterion for determining which families should undergo testing for MSH2 and MLH1 mutations. The Modified Amsterdam and the Amsterdam II criteria increase sensitivity, but still miss many families with mutations. The most sensitive clinical criteria for identifying subjects with pathogenic MSH2 and MLH1 mutations were the Bethesda Guidelines; a streamlined version of the Bethesda Guidelines may be more specific and easier to use in clinical practice.

Familial microsatellite-stable non-polyposis colorectal cancer: incidence and characteristics in a clinic-based population.

Rovella V, Carrara S, Crucitti SC, Coco C, Magistrelli P, Lucci-Cordisco E, Anti M, Neri G, Genuardi M.

Department of Internal Medicine and Geriatrics, Catholic University School of Medicine A. Gemelli, Rome, Italy.

Ann Oncol 2001 Jun;12(6):813-8 Abstract quote

BACKGROUND: About 15%-20% of colorectal cancers (CRCs) are familial. While a fraction of these arise in the context of hereditary syndromes, the causes underlying the majority of familial CRCs are not yet understood.

PATIENTS AND METHODS: Family history of cancer, clinical characteristics, and microsatellite instability (MSI) in a series of 100 consecutive CRC patients were evaluated.

RESULTS: Eighteen patients had a positive family history of CRC in a first-degree relative. Of these, two had a clinical diagnosis of familial adenomatous polyposis (FAP), and three were diagnosed with hereditary non-polyposis colorectal cancer (HNPCC) following results of MSI analysis. A diagnosis of HNPCC was also established in a fourth patient with early onset CRC, who had a second-degree relative with CRC, and whose tumor was positive for MSI. The remaining 13 familial CRCs did not show MSI in tumor DNA. The mean age at tumor diagnosis in patients with familial microsatellite-stable (MSS) CRC was higher than in HNPCC and FAP patients and similar to that recorded in sporadic cases. The incidence of second primary malignancies was significantly higher in familial MSS CRC probands (n = 4) compared to patients who did not have a diagnosis of FAP or HNPCC and did not have first-degree relatives affected with CRC (n = 6, in a total of 81 probands with these characteristics).

CONCLUSIONS: These results define the existence of a subset of familial CRCs characterized by relatively late age at onset, high incidence of second primary tumors, and absence of MSI in tumor DNA.


More differences between HNPCC-related and sporadic carcinomas from the endometrium as compared to the colon.

van den Bos M, van den Hoven M, Jongejan E, van der Leij F, Michels M, Schakenraad S, Aben K, Hoogerbrugge N, Ligtenberg M, van Krieken JH.

Departments of Pathology, Epidemiology and Human Genetics, University Medical Centre Nijmegen, The Netherlands.
Am J Surg Pathol. 2004 Jun;28(6):706-11. Abstract quote  

PURPOSE: Recognition of hereditary nonpolyposis colorectal cancer (HNPCC)-related endometrial carcinoma from sporadic carcinoma by histologic features as compared with colonic cases.

STUDY DESIGN: Case-control study.

METHODS AND MATERIALS: From the files of the Nijmegen Hereditary Cancer Clinic, HNPCC-related (n = 6) endometrial and colorectal (n = 18) carcinomas were selected. For every HNPCC-related tumor, 2 sporadic control cases were included. The tumors were evaluated for the following 7 pathologic features: tumor differentiation, T-stage, growth pattern, presence of Crohn-like lymphoid reaction, mucinous differentiation, presence of lymphangioinvasive growth, and the amount of tumor-infiltrating lymphocytes.

RESULTS: HNPCC-related endometrial carcinomas were significantly more often poorly differentiated (83% versus 27%), more often showed the presence of a Crohn-like lymphoid reaction (100% versus 13%) and lymphangioinvasive growth (67% versus 0%), and high number of tumor-infiltrating lymphocytes were more often present (100% versus 36%) compared with sporadic endometrial carcinomas. The differences between HNPCC and sporadic colorectal cancer specimens were less discriminating.

CONCLUSIONS: HNPCC-related endometrial carcinomas are characterized by poor differentiation, more frequent Crohn-like lymphoid reaction, lymphangioinvasive growth and more tumor-infiltrating lymphocytes. These features therefore might form the basis for selecting patients for counseling in a hereditary cancer clinic or testing for microsatellite instability or mutation analysis of mismatch repair genes, especially when they are of relatively young age.

Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer.

Shia J, Ellis NA, Paty PB, Nash GM, Qin J, Offit K, Zhang XM, Markowitz AJ, Nafa K, Guillem JG, Wong WD, Gerald WL, Klimstra DS.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10002, USA.

Am J Surg Pathol. 2003 Nov;27(11):1407-17. Abstract quote  

Identification of colorectal carcinomas with high levels of DNA microsatellite instability (MSI-H) is important because of the suggested prognostic and therapeutic significance associated with MSI.

The role of histology in identifying MSI-H colorectal carcinomas has been suggested by some studies but not confirmed by others. Furthermore, previous studies assumed that hereditary nonpolyposis colorectal cancer (HNPCC)-associated MSI-H tumors and sporadic MSI-H tumors have similar histology. This assumption, however, has been challenged by more recent studies.

In this report, we first analyzed the value of various histologic features in predicting MSI-H in a series of 218 colorectal carcinomas containing mixed HNPCC and sporadic cases [77 tumors (35%) were MSI-H by polymerase chain reaction (PCR) method]. Then, we evaluated the various histologic features comparatively in two groups extracted from the 218 cases. Group A was composed of 84 tumors from 82 patients obtained based on a strong family history (HNPCC/HNPCC-like group) (male to female ratio, 42:40; age range, 23-80 years, median, 53.5 years). Thirty-one of the 84 tumors (41.7%) were MSI-H by PCR, and all 31 cases were HNPCC by Amsterdam criteria. Group B was composed of 109 patients with no family history of colorectal cancer or HNPCC-associated cancer, obtained from surgical clinics (sporadic group) (male to female ratio, 65:69; age range, 31-84 years, median, 65 years). Thirty-five of the 109 tumors (32.1%) were MSI-H by PCR.

Our results showed that, overall, poor tumor differentiation, medullary type, mucinous type, signet-ring cell component, histologic heterogeneity, and increased tumor-infiltrating lymphocytes (TILs) were features more commonly seen in MSI-H tumors than in non-MSI-H tumors. Comparative analyses showed that the overall TIL count was significantly higher in HNPCC/HNPCC-like group, and mucinous type appeared to be more frequent in HNPCC MSI-H tumors than in sporadic MSI-H tumors. However, there was no significant difference in the odds ratio for predicting MSI-H status for any of the analyzed histologic features between HNPCC/HNPCC-like group and sporadic group, indicating that differences between HNPCC and sporadic MSI-H tumors did not significantly impact on the informative value of histology in predicting MSI in the two different clinical settings. TIL counts followed by histologic heterogeneity provided the greatest sensitivity and specificity in predicting MSI status in both HNPCC/HNPCC-like and sporadic cases.

Using a stepwise logistic regression model, a formula was generated that could be used to calculate the probability of a colorectal carcinoma being MSI-H based on morphologic features.


Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer.

Halvarsson B, Lindblom A, Johansson L, Lagerstedt K, Nilbert M.

1Department of Pathology, Lund University Hospital, Lund, Sweden.
Mod Pathol. 2005 Aug;18(8):1095-101. Abstract quote  

Colorectal adenomas occur at younger age, at increased frequency and have a greater tendency for malignant transformation in patients with hereditary nonpolyposis colorectal cancer (HNPCC).

We performed immunostaining for the mismatch repair proteins MLH1, PMS2, MSH2 and MSH6 in 35 colorectal adenomas from 26 patients with HNPCC and identified loss of immunostaining in 23/35 (0.66) adenomas. Loss of mismatch repair protein immunostaining was particularly frequent in large (>5 mm) (14/16) and proximally located (13/15) adenomas, whereas the gene mutated-MLH1 or MSH2-and the type of mutation did not seem to affect the results.

We conclude that loss of mismatch repair protein immunostaining is detected at a lower rate in adenomas than in carcinomas associated with HNPCC. Adenomatous tissue can thus be used for immunostaining of mismatch repair proteins in clinical investigations of HNPCC, but whereas loss of immunostaining may pinpoint the gene affected and thereby guide mutation analysis, retained staining cannot exclude that the adenoma developed as part of the syndrome due to reduced sensitivity. However, the analysis has a greater chance of being informative if large and proximally located adenomas are selected.
Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer.

Pinol V, Castells A, Andreu M, Castellvi-Bel S, Alenda C, Llor X, Xicola RM, Rodriguez-Moranta F, Paya A, Jover R, Bessa X; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association.

Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clinic, University of Barcelona, Barcelona, Spain.
JAMA. 2005 Apr 27;293(16):1986-94. Abstract quote  

CONTEXT: The selection of individuals for hereditary nonpolyposis colorectal cancer (HNPCC) genetic testing is challenging. Recently, the National Cancer Institute outlined a new set of recommendations, the revised Bethesda guidelines, for the identification of individuals with HNPCC who should be tested for microsatellite instability.

OBJECTIVE: To establish the most effective and efficient strategy for the detection of MSH2/MLH1 gene carriers.

DESIGN, SETTING, AND PATIENTS: A prospective, multicenter, nationwide study (the EPICOLON study) in 20 hospitals in the general community in Spain of 1222 patients with newly diagnosed colorectal cancer between November 1, 2000, and October 31, 2001.

INTERVENTIONS: Microsatellite instability testing and MSH2/MLH1 immunostaining in all patients regardless of age, personal or family history, and tumor characteristics. Patients whose tumors exhibited microsatellite instability and/or lack of protein expression underwent MSH2/MLH1 germline testing.

MAIN OUTCOME MEASURES: Effectiveness and efficiency of both microsatellite instability testing and immunostaining, either directly or previous selection of patients according to the revised Bethesda guidelines, were evaluated with respect to the presence of MSH2/MLH1 germline mutations.

RESULTS: Two hundred eighty-seven patients (23.5%) fulfilled the revised Bethesda guidelines. Ninety-one patients (7.4%) had a mismatch repair deficiency, with tumors exhibiting either microsatellite instability (n = 83) or loss of protein expression (n = 81). Germline testing identified 11 mutations (0.9%) in either MSH2 (7 cases) or MLH1 (4 cases) genes. Strategies based on either microsatellite instability testing or immunostaining previous selection of patients according to the revised Bethesda guidelines were the most effective (sensitivity, 81.8% and 81.8%; specificity, 98.0% and 98.2%; positive predictive value, 27.3% and 29.0%, respectively) to identify MSH2/MLH1 gene carriers. Logistic regression analysis confirmed the revised Bethesda guidelines as the most discriminating set of clinical parameters (odds ratio, 33.3; 95% confidence interval, 4.3-250; P = .001).

CONCLUSION: The revised Bethesda guidelines constitute a useful approach to identify patients at risk for HNPCC. In patients fulfilling these criteria, both microsatellite instability testing and immunostaining are equivalent and highly effective strategies to further select those patients who should be tested for MSH2/MLH1 germline mutations.

Conventional and tissue microarray immunohistochemical expression analysis of mismatch repair in hereditary colorectal tumors.

Hendriks Y, Franken P, Dierssen JW, De Leeuw W, Wijnen J, Dreef E, Tops C, Breuning M, Brocker-Vriends A, Vasen H, Fodde R, Morreau H.

Center for Human and Clinical Genetics and the Department of Pathology, Leiden University Medical Center, Leiden.


Am J Pathol 2003 Feb;162(2):469-77 Abstract quote

Immunohistochemistry (IHC) of mismatch repair (MMR) proteins in colorectal tumors together with microsatellite analysis (MSI) can be helpful in identifying families eligible for mutation analysis.

The aims were to determine sensitivity of IHC for MLH1, MSH2, and MSH6 and MSI analysis in tumors from known MMR gene mutation carriers; and to evaluate the use of tissue microarrays for IHC (IHC-TMA) of colon tumors in its ability to identify potential carriers of MMR gene mutations, and compare it with IHC on whole slides. IHC on whole slides was performed in colorectal tumors from 45 carriers of a germline mutation in one of the MMR genes. The TMA cohort consisted of 129 colon tumors from (suspected) hereditary nonpolyposis colorectal cancer (HNPCC) patients.

Whole slide IHC analysis had a sensitivity of 89% in detecting MMR deficiency in carriers of a pathogenic MMR mutation. Sensitivity by MSI analysis was 93%. IHC can also be used to predict which gene is expected to harbor the mutation: for MLH1, MSH2, and MSH6, IHC on whole slides would have correctly predicted the mutation in 48%, 92%, and 75% of the cases, respectively. We propose a scheme for the diagnostic approach of families with (suspected) HNPCC.

Comparison of the IHC results based on whole slides versus TMA, showed a concordance of 85%, 95%, and 75% for MLH, MSH2, and MSH6, respectively. This study therefore shows that IHC-TMA can be reliably used to simultaneously screen a large number of tumors from (suspected) HNPCC patients, at first in a research setting.

Correlation of mismatch repair genes immunohistochemistry and microsatellite instability status in HNPCC-associated tumours.

Ruszkiewicz A, Bennett G, Moore J, Manavis J, Rudzki B, Shen L, Suthers G.

Institute of Medical and Veterinary Science, Tissue Pathology, Royal Adelaide Hospital, Adelaide, South Australia.

Pathology 2002 Dec;34(6):541-7 Abstract quote

AIM: The aim of this study was to assess the performance of immunohistochemistry using antibodies for MLH1, MSH2, MSH6 and PMS2 mismatch repair gene proteins against microsatellite instability (MSI) testing.

METHODS: Tumour samples included in this study were derived from referred patients for screening for hereditary non-polyposis colorectal cancer (HNPCC) and patients who had resections for colorectal cancer that were examined at our institution. MSI was assessed at nine loci (BAT25, BAT26, BAT40, D2S123, D10S197, D17S579, D18S34, D5S346 and D17S250) in all cases. Immunohistochemistry for MLH1 and MSH2 was performed in all cases. Staining for MSH6 and PMS2 was performed in selected cases only.

RESULTS: There were 742 tumours including 661 colorectal lesions and 81 extracolonic tumours of the HNPCC spectrum. Among the 555 MSI-negative tumours, 554 showed an intact protein expression. Amongst the 187 MSI-positive tumours, 126 showed abnormal expression of MLH1 gene protein, 41 showed abnormal expression of MSH2 gene, three showed abnormal expression of MSH6 only, one showed abnormal expression of PMS2 gene protein only and one case showed abnormal expression of all four proteins.

CONCLUSION: Immunohistochemistry offers an alternative method for assessment of MSI status which is fast and relatively inexpensive compared with MSI testing. We achieved a sensitivity rate of 92% and specificity of 99.8% for immunohistochemistry testing assessed against the MSI testing. It has to be accepted that a small fraction of MSI-positive cases will be missed by testing with immunohistochemistry alone.

Immunohistochemical detection of mismatch repair gene proteins as a useful tool for the identification of colorectal carcinoma with the mutator phenotype.

Chaves P, Cruz C, Lage P, Claro I, Cravo M, Leitao CN, Soares J.

Department of Pathology, Instituto Portugues de Oncologia de Francisco Gentil, Lisboa, Portugal.

J Pathol 2000 Aug;191(4):355-60 Abstract quote

There are two well-defined pathways for colorectal carcinogenesis, the suppressor and the mutator pathways. The latter is characteristic of hereditary non-polyposis colorectal cancer (HNPCC), but can also be found in a subset of sporadic colorectal cancer (SCC) possessing distinctive clinical and pathological features, namely early age of onset, location in the right colon, poor differentiation, and a predominant mucinous component. This mutator pathway results from inactivation of mismatch repair (MMR) genes, namely MSH2 and MLH1.

The aim of this study was to ascertain if abnormal MMR protein gene expression is a good indicator for identifying tumours from the mutator pathway. Seventy-six cases of SCC were studied by immunohistochemistry using two monoclonal mouse antibodies that react against MSH2 and MLH1 protein gene products. Immunoexpression was assessed both in tumour and in non-neoplastic, adjacent and distant mucosa. Microsatellite instability (MSI) was detected by evaluating the length of poly(CA) repeated sequences at seven loci, or by the detection of small unstable alleles in a poly(A) repeat - BAT-26. Except for BAT-26, in which only tumour DNA was used, MSI analysis was performed in both tumour and normal mucosal DNA. MSI was classified as high (MSI-H), low (MSI-L) or stable (MSS). Abnormal protein expression was found in 9/76 (12%) tumours.

Immunohistochemistry for hmlh1 and hmsh2 detected 75% of MSI-H. There was also a highly significant correlation between the observed immunoexpression and several clinical and pathological characteristics described as the phenotypic profile of the mutator pathway, such as right-sided location (p=0.003), mucin production (p=0.008), and a peritumoural lymphoid infiltrate (p=0.009). Non-neoplastic adjacent mucosa showed normal hMSH2 expression in all cases, but in ten cases there was no hMLH1 expression in this transitional mucosa, which is known to display an alterated mucin pattern and a high proliferative rate.

These results demonstrated a good correlation between hMLH1 and hMSH2 gene immunoexpression and the clinico-pathological features characteristic of the mutator phenotype and support the use of this method as a rapid and efficient way to detect tumours arising from this pathway.



Very low incidence of microsatellite instability in rectal cancers from families at risk for HNPCC.

Hoogerbrugge N, Willems R, Van Krieken HJ, Kiemeney LA, Weijmans M, Nagengast FM, Arts N, Brunner HG, Ligtenberg MJ.

Department of Human Genetics, University Medical Center Nijmegen, the Netherlands.

Clin Genet 2003 Jan;63(1):64-70 Abstract quote

In families at risk for hereditary non-polyposis colorectal cancer (HNPCC) that do not fulfill all clinical criteria for HNPCC, additional evidence is sought by testing cancer specimens for microsatellite instability (MSI).

We investigated whether the location of a colorectal cancer (CRC) predicts the result of MSI-testing in these families. One hundred and seven patients suspected for HNPCC were offered MSI-testing. MSI-testing was positive in 6/7 patients with endometrial carcinoma and in 22/100 patients with CRC. Only one out of 22 (4%) rectal cancers was MSI-positive, and in this patient no mismatch repair (MMR) gene mutation was found. Right-sided colon carcinomas were more likely to be MSI-positive (14/37 or 38%), followed by left-sided colon carcinomas (7/4 or 17%) (p < 0.05), with 6/14 and 4/7 MMR gene mutations, respectively. The likelihood that a tumor would be MSI-positive was 3.3 times greater for right-sided than for left-sided colon cancer (OR 3.3, p < 0.05).

Microsatellite instability was 8.1 times more frequent in colon cancers than in rectal cancers (p < 0.05). The presence of MSI was independently related to fulfillment of the Bethesda criteria (OR 7.0, p = 0.01). In families with multiple cases of colorectal cancer, the rectal cancers are only rarely MSI-positive. This indicates that even in families with multiple colorectal cancers, rectal cancers are most commonly of sporadic origin.

Germline characterization of early-aged onset of hereditary non-polyposis colorectal cancer.

Huang SC, Lavine JE, Boland PS, Newbury RO, Kolodner R, Pham TT, Arnold CN, Boland CR, Carethers JM.

Division of Gastroenterology and Nutrition, Department of Pediatrics, University of California, San Diego, California, USA.

J Pediatr 2001 May;138(5):629-35 Abstract quote

OBJECTIVES: Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by the early onset of colorectal cancer (approximately 40 years). Adolescent colorectal cancer is unusual in HNPCC families. We speculated that some DNA mismatch repair germline mutations might be associated with early onset of disease.

STUDY DESIGN: Genomic DNA was extracted from members of a kindred with virulent HNPCC fitting the Amsterdam Criteria for HNPCC and sequenced for 2 DNA mismatch repair genes, hMSH2 and hMLH1. A sigmoid adenocarcinoma from the 14-year-old proband was analyzed for highfrequency microsatellite instability and immunostained for DNA mismatch repair gene expression.

RESULTS: A germline mutation was identified at nucleotide 676 (codon 226) of the hMLH1 gene. The C to T transition created a nonsense mutation, truncating the hMLH1 protein. This mutation also alters the splice donor sequence, because nucleotide 676 is 2 base pairs from the 3' end of the exon 8. The proband's tumor demonstrated high-frequency microsatellite instability and displayed loss of hMLH1 expression, indicating bi-allelic inactivation of hMLH1.

CONCLUSIONS: A complex mutation of hMLH1 at codon 226 is associated with adolescent onset of colorectal cancer in an HNPCC family. Genetic screening of other suspected HNPCC families with unusually young members with cancer might reveal certain genotypes with particularly virulent forms of this disease.

A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer.

Maillet P, Chappuis PO, Vaudan G, Dobbie Z, Muller H, Hutter P, Sappino AP.

Unit of Identification of Genetic Predisposition to Cancer, Division of Oncology, HUG, Geneva Switzerland.

Int J Cancer 2000 Dec 15;88(6):928-31 Abstract quote

Germ-line mutations in MLH1 and MSH2 genes predispose to hereditary non-polyposis colorectal cancer (HNPCC) syndrome, but they do not predict a specific phenotype of the disease.

We speculated that the ataxia-telangiectasia mutated gene (ATM) was a candidate gene to modulate the phenotypic expression of HNPCC, as heterozygous individuals for germ-line ATM mutations have been considered at higher risk of developing epithelial malignancies. The frequency of the ATM D1853N polymorphism was evaluated in 167 individuals from 20 HNPCC families in which MLH1 or MSH2 germ-line mutations co-segregated with the disease. Among the 67 MLH1 or MSH2 mutation carriers, the ATM 1853N variant was associated with a significantly higher incidence of colorectal and other HNPCC-related cancers, when compared with individuals carrying the ATM 1853D variant [12/13 (92%) vs. 31/54 (57.5%); p = 0.02]. MLH1 and MSH2 mutation carriers who concomitantly carried the ATM 1853N variant, had an 8 times increased risk of developing colorectal and other HNPCC-related cancers (OR: 8.9; p = 0.02), when compared with MLH1 or MSH2 mutation carriers with the ATM 1853D variant.

Our results suggest that the ATM D1853N polymorphism modulates the penetrance of MLH1 and MSH2 germ-line mutations.


Heritable colorectal cancer syndromes: recognition and preventive management.

Boardman LA.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.

Gastroenterol Clin North Am 2002 Dec;31(4):1107-31 Abstract quote

Familial CRC syndromes account for a small yet important portion of colorectal malignancies. HNPCC, FAP, JPS, and Peutz-Jeghers syndrome are the four major conditions to r to consider if an hereditary condition is suspected in an individual with CRC.

A multidisciplinary team comprised of a medical geneticist, gastroenterologist, pathologist, radiologist, and colorectal surgeon with expertise in recognizing and establishing the diagnosis of a specific familial cancer condition is crucial to implementing the proper management and prevention strategies unique to each of these syndromes. Genetic testing for each of these coniditions is available and useful for presymptomatic diagnosis and for indicated surveillance regimens. Vigilant endoscopic surveillance and careful timing of surgery are the mainstays of prevention for gastrointestinal malignancies.

But with the advancement of genetic evaluation, improved cancer surveillance for intestinal as well as extraintestinal cancer, and chemopreventive strategies, the management of patients with a familial CRC syndrome will continue to evolve and, hopefully, significantly reduce their cancer burden.

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