Germ Line Mutations of Mismatch Repair Genes in Hereditary Nonpolyposis Colorectal Cancer Patients with Small Bowel Cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study

Park, Jae Gahb; Kim, Duck Woo; Hong, Chang Won; Nam, Byung Ho; Shin, Young Kee; Hong, Sung Hye; Kim, Il Jin; Lim, Sangwoo; Aronson, Melyssa; Bisgaard, Marie Luise; Brown, Gregor J.; Burn, John; Chow, Elizabeth; Conrad, Peggy; Douglas, Fiona; Dunlop, Malcolm G.; Ford, James M.; Greenblatt, Marc S.; Heikki, Jarvinen; Heinimann, Karl; Lynch, Elly; Macrae, Finlay; McKinnon, Wendy; Möeslein, Gabriela; Rossi, Mauro; Rozen, Paul; Schofield, Lyn; Vaccaro, Carlos; Vasen, Hans F. A.; Velthuizen, Mary E; Viel, Alessandra; Wijnen, Juul T.

doi:10.1158/1078-0432.ccr-05-2452

Cited by 41 publications

(30 citation statements)

References 22 publications

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“…Even rare cancers such as that of the small intestine were diagnosed early, the youngest diagnosed in our study was at age 36 years, although these cancers have been described in previous studies [19] to develop in the early teenage years. Sarcomas are rarely described as part of the HNPCC spectrum; however our study has seen an eight fold increase over the population average for this type of tumour suggesting that sarcomas could indeed be part of the spectrum of cancers involved in Lynch syndrome, as previously suggested by Arana et al in 2002 [20].…”

Section: Discussioncontrasting

confidence: 51%

Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC)

et al. 2007

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The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at diagnosis of first CRC in MSH6 mutation families was 59 years compared to 45 years in both MLH1 and MSH2 mutation families. The relative risk (RR) of endometrial cancer was 55 in MSH2 mutation families, compared with 27 in MLH1 mutation families, and 37 in MSH6 mutation families; median age at diagnosis 49 years. Even within MSH2 families, endometrial cancer tended to cluster, with 28 of the 58 cases coming from families with three or more cases (P < 0.001). Absolute risk of endometrial cancer in MLH1 families was still greater than any other cancer (other than CRC). 5% of cancers in both MLH1 and MSH2 mutation families were gastric (RR = 12); 53% of these were diagnosed before 50 years. Seven cases of small intestinal cancer occurred in MSH2 and MLH1 mutation families (RR = 26). There were 13 cases of cancer of the ureter; all were in MSH2 families. These cancers tended to cluster within families (P < 0.001); three of seven families with urothelial cancer had such cases in two or more individuals; two others had kidney cancer. Nineteen of 27 ovarian cancers (70%) were in MSH2 mutation families and 70% of these were diagnosed before age 50 years. There were 9 cases of sebaceous skin cancer, 3 in two MLH1 and 6 in four MSH2 mutation families. Of 22 pancreatic cancers, 14 were known to be diagnosed before 60 years. Breast cancer RR was 1.7 overall. The type of mutation (truncating or other type, and site of mutation) showed no obvious correlation with the presence or absence of extra-colonic cancers in families.

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Section: Discussioncontrasting

confidence: 51%

Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC)

et al. 2007

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“…However, certain single-amino acid substitutions can yield partially active, dominant-negative, unstable, or nonfunctional proteins, depending on the nature of the individual mutations. Defective MMR caused by missense mutations can result from loss of enzymatic activity (ATP binding/hydrolysis) [1]; defective protein-protein interaction (complex formation) [2]; defective protein-DNA binding (mismatch recognition) [3]; aberrant MMR protein subcellular localization [4]; altered MMR protein expression (stoichiometry of MMR complexes) [5]; or [6] altered MMR protein stability. Recently, Drost et al (16) described a new cell-free assay for functional analysis of missense mutations in MLH1.…”

Section: Discussionmentioning

confidence: 99%

“…Affected individuals are at increased risk for developing colorectal cancer and extra-colonic carcinomas, including cancers of the endometrium, ovary, urothelium, and stomach (3). HNPCC is characterized by germline mutations in mismatch repair (MMR) genes, including MLH1 (MIM#120436), MSH2 (MIM#120435), PMS1 (MIM# 600258), PMS2 (MIM #600259), and MSH6 (MIM #600678) (4)(5)(6). About 90% of the germline mutations identified in these MMR genes occur in MLH1 and MSH2 (7).…”

Section: Introductionmentioning

confidence: 99%

Three novel germline mutations in MLH1 and MSH2 in families with Lynch syndrome living on Jeju island, Korea

Kim¹,

Choe²,

KimCho³

et al. 2010

BMB Reports

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Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome characterized by predisposition to early-onset cancers. HNPCC is caused by heterozygous loss-of-function mutations within the mismatch repair genes MLH1, MSH2, MSH6, PMS1, and PMS2. We genotyped the MLH1 and MSH2 genes in patients suffering from Lynch syndrome and in 11 unrelated patients who were diagnosed with colorectal cancer and had subsequently undergone surgery. Five Lynch syndrome patients carried germline mutations in MLH1 or MSH2. Two of these were identified as known mutations in MLH1: deletion of exon 10 and a point mutation (V384D). The remaining three patients exhibited novel mutations: a duplication (937_942dupGAAGTT) in MLH1; deletion of exons 8, 9, and 10; and a point mutation in MLH1 (

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“…Of these, the MLH1 and MSH2 mutations account for 70-90% of the families with LS. [5][6][7][8][9][10][11] Endometrial cancer is the most common site for extracolonic malignancies in LS patients. It has even been reported that the incidence of endometrial carcinoma surpasses the incidence of CRC in female LS patients.…”

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confidence: 99%

Is surveillance of the small bowel indicated for Lynch syndrome families?

Kate

Kleibeuker

Nagengast

et al. 2007

Gut

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Background: Small bowel cancer (SBC) is one of the tumours associated with Lynch syndrome (LS). To advise on screening for this tumour it is paramount to be informed about the lifetime risk. The aim of this study was to calculate the lifetime risk of SBC in LS and to identify possible risk factors. Methods: Clinical and pathological data were collected on 1496 proven or putative carriers of a mismatch repair gene mutation from 189 families. Kaplan-Meier survival analysis was used to calculate the lifetime risk and to assess potential risk factors. Results: 28 (1.9%) of the 1496 (putative) mutation carriers were identified with SBC. The median age at diagnosis was 52 years (range 23-69 years). The lifetime risk of developing SBC was 4.2%. There was no difference in risk between males and females (log rank: p = 0.2470), or between MLH1 and MSH2 mutation carriers (log rank: p = 0.2754). SBC was not observed in MSH6 mutation carriers (n = 203). The previous occurrence of colorectal cancer and a family history of SBC did not increase the risk significantly.Conclusions: Approximately, one out of 25 mutation carriers will develop SBC during life. No specific risk factors were identified. The risk appeared to be too low to advise screening by means of an invasive burdensome procedure like double balloon enteroscopy. However, screening by a non-invasive procedure (videocapsule endoscopy) might be considered if future studies will show its cost effectiveness. In patients with unexplained abdominal complaints and/or unexplained iron deficiency anaemia SBC should be considered.

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Germ Line Mutations of Mismatch Repair Genes in Hereditary Nonpolyposis Colorectal Cancer Patients with Small Bowel Cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study

Cited by 41 publications

References 22 publications

Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC)

Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC)

Three novel germline mutations in MLH1 and MSH2 in families with Lynch syndrome living on Jeju island, Korea

Is surveillance of the small bowel indicated for Lynch syndrome families?

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