An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC

Goldberg, Yael; Porat, Rinnat M.; Kedar, Inbal; Shochat, Chen; Galinsky, Daliah; Hamburger, Tamar; Hubert, Ayala; Strul, Hana; Kariiv, Revital; Ben-Avi, Liat; Savion, Moran; Pikarsky, Eli; Abeliovich, Dvorah; Bercovich, Dani; Lerer, Israela; Peretz, Tamar

doi:10.1007/s10689-009-9298-9

Cited by 19 publications

(14 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, in only a few of the described, ethnically diverse families that harbor MSH6 mutations, gastric or pancreatic cancer are mentioned as part of the tumorous phenotype. Specifically, none of 378 Dutch MSH6 mutation carriers developed gastric cancer [17] with similar data in a large French study encompassing 537 families with 33 MSH6 mutation carriers [11] and none of the Israeli MSH6 3984dup4 mutation carriers had gastric cancer [18]. Yet, gastric cancer was the most commonly reported extra-colonic cancer among Chinese HNPCC families [7].…”

Section: Discussionsupporting

confidence: 66%

The founder Ashkenazi Jewish mutations in the MSH2 and MSH6 genes in Israeli patients with gastric and pancreatic cancer

et al. 2012

View full text Add to dashboard Cite

The genetic basis for gastric and pancreatic cancer is largely undetermined. These cancers are overrepresented in hereditary non polyposis colon cancer (HNPCC), inherited cancer syndrome attributed to germline mutations primarily in the MSH2, MLH1 and MSH6 genes. Among Ashkenazi Jewish HNPCC cases, recurring mutations in the MSH2 (1906G>C; A636P) and MSH6 (c.3984_3987dupGTCA; c.3959_3962delCAAG) genes can be detected. The MSH6*c.3984_3987dupGTCA mutation was recently detected in an Ashkenazi family with inherited gastric cancer. We hypothesized that it may be possible to detect the recurring MSH2 and MSH6 mutations in Jewish individuals with familial and sporadic gastric and pancreatic cancer. To test this notion, we genotyped 143 unrelated Jewish Israeli patients with gastric (n = 23) and pancreatic (n = 120) cancer. The majority of cases (100/143-70%) were Ashkenazi Jews, and 10% (n = 16)--of mixed Ashkenazi-non Ashkenazi Jewish ancestry, and most participants (n = 96-67.1%) had a positive family history of cancer. Genotyping the MSH2*A636P mutation was performed by PCR followed by restriction enzyme digest, and the MSH6*c.3984_3987dupGTCA and c.3959_3962delCAAG mutations were detected by fragment size analysis by capillary electrophoresis and sequencing. None of the participants harbored any of the genotyped MSH2 or MSH6 mutations. We conclude that the recurring Ashkenazi MSH2 and MSH6 mutations contribute little if any to sporadic and familial gastric and pancreatic cases in Israeli patients.

show abstract

Section: Discussionsupporting

confidence: 66%

The founder Ashkenazi Jewish mutations in the MSH2 and MSH6 genes in Israeli patients with gastric and pancreatic cancer

et al. 2012

View full text Add to dashboard Cite

show abstract

“…This is a major extension of previous publications (11,13). This is a major extension of previous publications (11,13).…”

supporting

confidence: 61%

Genetic features of Lynch syndrome in the Israeli population

et al. 2014

View full text Add to dashboard Cite

Diagnosis of Lynch syndrome (LS) may be complex. Knowledge of mutation spectrum and founder mutations in specific populations facilitates the diagnostic process. Aim of the study is to describe genetic features of LS in the Israeli population and report novel and founder mutations. Patients were studied at high-risk clinics. Diagnostics followed a multi-step process, including tumor testing, gene analysis and testing for founder mutations. LS was defined by positive mutation testing. We diagnosed LS in 242 subjects from 113 families coming from different ethnicities. We identified 54 different mutations; 13 of them are novel. Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2; 27% of the MSH2 mutations were large deletions. Seven founder mutations were detected in 61/113 (54%) families. Constitutional mismatch repair deficiency (CMMR-D) was identified in five families. Gene distribution in the Israeli population is unique, with relatively high incidence of mutations in MSH2 and MSH6. The mutation spectrum is wide; however, 54% of cases are caused by one of seven founder mutations. CMMR-D occurs in the context of founder mutations and consanguinity. These features should guide the diagnostic process, risk estimation, and genetic counseling.

show abstract

“…Mutations in the EPCAM gene, located upstream of MSH2, represent an additional cause that is estimated to contribute to 1-3% of the disease-predisposing mutations (10)(11)(12). Founder effects, i.e., mutations that are overrepresented within a geographically or ethically isolated population, have been described in several populations, such as in the different Scandinavian populations (8,13,14) and in the Ashkenazi Jewish population (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

et al. 2016

View full text Add to dashboard Cite

Abstract. Lynch syndrome caused by constitutional mismatch-repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6.Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.

show abstract

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC

Cited by 19 publications

References 19 publications

The founder Ashkenazi Jewish mutations in the MSH2 and MSH6 genes in Israeli patients with gastric and pancreatic cancer

The founder Ashkenazi Jewish mutations in the MSH2 and MSH6 genes in Israeli patients with gastric and pancreatic cancer

Genetic features of Lynch syndrome in the Israeli population

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

Contact Info

Product

Resources

About