NCI CANCERLIT^® Search: Non-polyposis Colon Cancer, Hereditary - September 2001

Last Modified: November 1, 2001

CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer.
Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability.
DNA variants of BAT-25 in Japanese, a locus frequently used for analysis of microsatellite instability.
Microsatellite instability: application in hereditary non-polyposis colorectal cancer.
Molecular genetics and endometrial cancer.
Gynecological tumors in hereditary nonpolyposis colorectal cancer: We know they are common--now what?
The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.
Immunohistochemistry for MSH2 and MHL1: a method for identifying mismatch repair deficient colorectal cancer.
Alterations of repeated sequences in 5' upstream and coding regions in colorectal tumors from patients with hereditary nonpolyposis colorectal cancer and Turcot syndrome.
Clinical and biologic heterogeneity of hereditary nonpolyposis colorectal cancer.
Comparison of Alu-PCR, microsatelite instability, and immunohistochemical analyses in finding features characteristic for hereditary nonpolyposis colorectal cancer.

CancerMail from the National Cancer Institute

1
UI - 21397945
AU - Bala S; Peltomaki P
TI - CYCLIN D1 as a genetic modifier in hereditary nonpolyposis colorectal cancer.
SO - Cancer Res 2001 Aug 15;61(16):6042-5
AD - Division of Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Hereditary nonpolyposis colorectal cancer is associated with inherited defects in DNA mismatch repair. Clinical variation even in cases with identical predisposing mutations suggests the existence of other factors contributing to the phenotype. We addressed the modifying role of the common A/G polymorphism in exon 4 and the alternatively spliced transcripts a and b of the CCND1 gene encoding cyclin D1 in a series of 146 affected carriers of 10 MLH1 and 3 MSH2 mutations. No correlation was observed between a particular allele (A versus G) and age at onset. However, the presence of the variant transcript b in blood/normal mucosa, by multiplex reverse transcription-PCR, was associated with a significantly lower age at onset of colon cancer as compared with individuals with transcript a only (35 versus 46 years; P = 0.02). Whereas our data do not support a modifying role of A versus G allele of CCND1, the results do suggest that the relative abundance of a and b transcripts may modify the age at onset of colon cancer in hereditary nonpolyposis colorectal cancer.

2
UI - 21397946
AU - Mori Y; Yin J; Rashid A; Leggett BA; Young J; Simms L; Kuehl PM; Langenberg P; Meltzer SJ; Stine OC
TI - Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability.
SO - Cancer Res 2001 Aug 15;61(16):6046-9
AD - Department of Medicine, University of Maryland School of Medicine, Baltimore V. A. Hospital, Baltimore, Maryland 21201, USA.
Coding region frameshift mutation caused by microsatellite instability (MSI) is one mechanism contributing to tumorigenesis in cancers with MSI in high frequency. Mutation of TGFBR2 is one example of this process. To identify additional examples, a large-scale genomic screen of coding region microsatellites was conducted. 1115 coding homopolymeric loci with six or more nucleotides were identified in an online genetic database. Mutational screening was performed at 152 of these loci in 46 colorectal tumors with MSI in high frequency. Nine loci were mutated in > or =20% of tumors, 10 loci in 10-20%, 24 loci in 5-10%, 43 loci in <5%, and 66 loci were not mutated in any tumors. The most frequently mutated novel loci were the activin type II receptor gene (58.1%), SEC63 (48.8%), AIM 2 (47.6%), a gene encoding a subunit of the NADH-ubiquinone oxidoreductase complex (27.9%), a homologue of mouse cordon-bleu (23.8%), and EBP1/PA2G4 (20.9%). This genome-wide approach identifies coding region MSI in genes or pathways not implicated previously in colorectal tumorigenesis, which may merit functional study or other additional analysis.

3
UI - 21410099
AU - Ichikawa A; Sugano K; Fujita S
TI - DNA variants of BAT-25 in Japanese, a locus frequently used for analysis of microsatellite instability.
SO - Jpn J Clin Oncol 2001 Jul;31(7):346-8
AD - Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center, Tochigi, Japan.
BAT-25 is a DNA marker, intragenic to the c-kit protooncogene, assigned to 4q12, containing a polythymine tract, mostly repeats of 25 poly(T) (T25). The BAT-25 locus is frequently used in the analysis of microsatellite instability (MSI) in cancer tissues. The number of poly(T) repeats at BAT-25 is reported to be quasi-monomorphic and this property permits the easy identification of the MSI status. We report DNA variants of BAT-25, in one patient with hereditary nonpolyposis colorectal cancer presenting T21 and T25 alleles and another carrying T18 and T25 alleles in the analysis of 100 normal Japanese donors. Observed allelic frequencies were 0.5% for both T21 and T18 alleles. So far, DNA variants of BAT-25 locus have been reported in African Americans with relatively high frequencies, but not in Japanese.

4
UI - 21193588
AU - Saletti P; Edwin ID; Pack K; Cavalli F; Atkin WS
TI - Microsatellite instability: application in hereditary non-polyposis colorectal cancer.
SO - Ann Oncol 2001 Feb;12(2):151-60
AD - Istituto Oncologico della Svizzera Italiana, Oncologia medica, Ospedale S. Giovanni, Bellinzona, Switzerland. oncosg@siak.ch
Colorectal cancer (CRC) is a significant cause of mortality in Western populations. About 15% of CRC patients report a family history of the disease. Studies on individuals with a genetic predisposition to CRC have been responsible for significant advances in the understanding of this disease. Thus, although developments in molecular biology have been mainly restricted to a minority of individuals with a hereditary background, information obtained from this group may affect the diagnosis and therapy of sporadic CRCs as well. Deficiency in the DNA mismatch repair (MMR) system results in microsatellite instability (MSI). Individuals from hereditary non-polyposis colorectal cancer (HNPCC) kindreds with germline mutations in genes involved in MMR may benefit from clinical screening programs. The higher frequency of MSI in HNPCC than in sporadic tumours suggests that involvement of MMR genes in sporadic adenomas may be uncommon. Consequently

5
UI - 21369414
AU - Lalloo F; Evans G
TI - Molecular genetics and endometrial cancer.
SO - Best Pract Res Clin Obstet Gynaecol 2001 Jun;15(3):355-63
AD - Department of Clinical Genetics, St Mary's Hospital, Hathersage Rd, Manchester, M13 0JH, UK.
Endometrial cancer is the ninth most common malignancy in females. Inherited forms of this malignancy exist. Mutations in mismatch repair genes result in hereditary non-polyposis colorectal cancer, which confers a lifetime risk of bowel cancer between 60-80% and an endometrial cancer risk of up to 60%. Current screening involves the use of transvaginal ultrasound and hysteroscopy. Genetic testing for mutations in the mismatch repair genes is available, and if a pathogenic change is found within a family, predictive testing becomes available for unaffected family members. If blood samples from family members are unavailable, tumour blocks may be studied to assess microsatellite instability, a feature of mismatch repair gene mutations.While mutations in the mismatch repair genes are found in inherited endometrial cancer they are rarely seen in sporadic cancers. However, there are a range of somatic gene mutations that are currently being studied in order to provide insight into the pathogenesis of endometrial cancer. Copyright 2001 Harcourt Publishers Ltd.

6
UI - 21423687
AU - Lu KH; Broaddus RR
TI - Gynecological tumors in hereditary nonpolyposis colorectal cancer: We know they are common--now what?
SO - Gynecol Oncol 2001 Aug;82(2):221-2

7
UI - 21423688
AU - Watson P; Butzow R; Lynch HT; Mecklin JP; Jarvinen HJ; Vasen HF; Madlensky L; Fidalgo P; Bernstein I; International Collaborative Group on HNPCC
TI - The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer.
SO - Gynecol Oncol 2001 Aug;82(2):223-8
AD - Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
OBJECTIVE: Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. METHODS:. Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. RESULTS: Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. CONCLUSIONS: Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage. Copyright 2001 Academic Press.

8
UI - 21270309
AU - Stone JG; Robertson D; Houlston RS
TI - Immunohistochemistry for MSH2 and MHL1: a method for identifying mismatch repair deficient colorectal cancer.
SO - J Clin Pathol 2001 Jun;54(6):484-7
AD - Section of Cancer Genetics, Institute of Cancer Genetics, Sutton, Surrey ,UK.
Colorectal cancers with DNA mismatch repair (MMR) gene mutations characteristically display a high rate of replication errors in simple repetitive sequences detectable as microsatellite instability (MSI). Most are the result of somatic MMR dysfunction; however, a subset are caused by germline mutations. The availability of commercial antibodies for MSH2 and MLH1 [corrected] offers an alternative strategy to molecular methods for identifying MMR deficient cancers. To evaluate immunohistochemistry, MLH1 and MSH2 expression was studied using monoclonal antibodies in formalin fixed, paraffin wax embedded cancers. The immunohistochemical staining patterns of 23 cancers displaying MSI, including four cases with germline mutations, were compared with 23 microsatellite stable (MSS) cancers. All MSS cancers exhibited staining with both antibodies. Twenty two of the MSI cases showed absent MMR expression with either anti-MSH2 or anti-MLH1 [corrected]. The high sensitivity and predictive value of immunohistochemistry in detecting MMR deficiency offers a method of discriminating between MSI and MSS cancers caused by MSH2 and MLH1 [corrected] dysfunction. The application and suitability of immunohistochemistry for the detection of MSI and as a strategy for prioritising the mutational analysis of MMR genes in routine clinical practice is discussed.

9
UI - 21417675
AU - Miyaki M; Iijima T; Shiba K; Aki T; Kita Y; Yasuno M; Mori T; Kuroki T; Iwama T
TI - Alterations of repeated sequences in 5' upstream and coding regions in colorectal tumors from patients with hereditary nonpolyposis colorectal cancer and Turcot syndrome.
SO - Oncogene 2001 Aug 23;20(37):5215-8
AD - Hereditary Tumor Research Project, Tokyo Metropolitan Komagome Hospital, Tokyo 113-8677, Japan. mmiyaki@opal.famille.ne.jp
One of the characteristics of tumors from patients with germline mutations of DNA mismatch repair genes is instability at microsatellite regions (MSI). We analysed alterations at repeated sequences of coding regions, as well as those of 5' upstream regions, in 29 MSI-High colorectal tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) and Turcot syndrome. We found that repeated sequences in 5' upstream regions were altered in these tumors, at considerable frequencies. The (A)10 repeat in the promoter region (position -178 to approximately -169) of the GAPDH gene was altered in 17% of the tumors. The (A)10(TA)9 in the 5' upstream region (position -318 to approximately -291) of the mitochondrial isoleucyl tRNA synthetase gene (IleRS-A), coded in nuclear DNA, was altered in 59% of the tumors, whereas (A)9 in the 5' upstream region (position -859 to approximately -851) of cytoplasmic isoleucyl tRNA synthetase gene (IleRS-B) was not altered. Alteration at repeated sequences in the coding regions were 72% at TGFbetaRII(A)10, 24% at IGFIIR(G)8, 45% at BAX(G)8, 55% at E2F4(CAG)13, 66% at caspase-5 (A)10, 31% at MBD4(A)10, 55% at hMSH3(A)8 and 34% at hMSH6(C)8. The number of altered genes increased with the advancement of carcinoma according to Dukes categories: mean numbers of altered genes within these 10 genes were 2.6 for Dukes A, 4.7 for Dukes B and 7.8 for Dukes C. The mean number for adenomas was 2.0. These results suggest that the MSI phenotype also causes alteration of 5' upstream regions which may affect apoptosis and some mitochondrial functions in HNPCC and Turcot tumors, and that accumulation of altered genes with repeated sequences is associated with the progression of HNPCC and Turcot colorectal tumors.

10
UI - 21385093
AU - Benatti P; Roncucci L; Ganazzi D; Percesepe A; Di Gregorio C; Pedroni M; Borghi F; Sala E; Scarselli A; Menigatti M; Rossi G; Genuardi M; Viel A; Ponz De Leon M
TI - Clinical and biologic heterogeneity of hereditary nonpolyposis colorectal cancer.
SO - Int J Cancer 2001 Sep 20;95(5):323-8
AD - Department of Internal Medicine, Universita di Modena e Reggio Emilia, via del Pozzo 71, 41100 Modena, Italy. pbenatti@unimo.it
MMR gene mutations and MSI are not found in all clinically diagnosed HNPCC families. We evaluated whether MMR genotyping and tumor MSI analysis could identify distinct clinical subgroups among HNPCC families. Twenty-nine clinical HNPCC families were divided into 3 groups: A, families with hMLH1 or hMSH2 gene mutations; B, MMR gene mutations not present but MSI present in at least 50% of tumors tested; C, mutational and MSI analyses negative. We evaluated tumor spectrum, age at onset, risk of cancer in the follow-up and survival for CRC in the 3 groups. Tumors of the target organs in HNPCC (colon and rectum, endometrium, ovary, small bowel, stomach, renal pelvis and ureter) were more frequent in the first 2 groups than in the latter. Colon cancer was more frequently located in the proximal colon and showed an earlier age at onset in families with MMR gene mutation or with MSI than in families with stable tumors. Comparing the occurrence of tumors in the follow-up, in the first 2 groups patients younger than 50 years had a higher RR, which was particularly marked for CRC (RR = 18.6 for group A vs. group C, RR = 16.7 for group B vs. group C). CRC patients in the first 2 groups had a better clinical prognosis. The results of molecular analysis could distinguish, within clinically defined HNPCC families, different subgroups to which specific programs of surveillance could be addressed. Copyright 2001 Wiley-Liss, Inc.

11
UI - 21454309
AU - Debniak T; Gorski B; Cybulski C; Jakubowska A; Kurzawski G; Kladny J; Lubinski J
TI - Comparison of Alu-PCR, microsatelite instability, and immunohistochemical analyses in finding features characteristic for hereditary nonpolyposis colorectal cancer.
SO - J Cancer Res Clin Oncol 2001 Sep;127(9):565-9
AD - Department of Genetics and Pathology, Pomeranian Medical University, Poland. debniak@poczta.wp.pl
PURPOSE: To evaluate and compare alterations detected by Alu-PCR, microsatellite instability (MI), and absence of hMLH1 and hMSH2 protein expression measured by immunohistochemical (IHC) analyses as features characteristic of hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: Alu-PCR, MI, and IHC analyses were performed in two groups of patients: (A) HNPCC diagnosed definitively or with high probability (11 patients); (B) sporadic late-onset colorectal cancers (15 patients). RESULTS: Quantitative alterations recorded by Alu-PCR were not characteristic for Lynch syndrome, occurring more frequently in sporadic late-onset CRC (73% in group B vs 45% in group A). Qualitative changes (occurrence of additional peaks or shifts) have been found to be associated with HNPCC with odds ratio (OR) 2.4, specificity approximately 70% and sensitivity approximately 55%. Findings in MI and IHC analyses have been recognized as features more characteristic of HNPCC suggesting Lynch syndrome with OR 4.8, specificity approximately 80%, sensitivity approximately 55% (MI) and OR 8.0, specificity approximately 93%, sensitivity approximately 36% (IHC). CONCLUSION: Molecular techniques allowing identification of patients with a high probability of having HNPCC include IHC and MI analyses. Our results suggest that their replacement by Alu-PCR analysis in diagnosis of HNPCC is not justified.