Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome Journal Article

   


Authors: Raskin, L.; Schwenter, F.; Freytsis, M.; Tischkowitz, M.; Wong, N.; Chong, G.; Narod, S. A.; Levine, D. A.; Bogomolniy, F.; Aronson, M.; Thibodeau, S. N.; Hunt, K. S.; Rennert, G.; Gallinger, S.; Gruber, S. B.; Foulkes, W. D.
Article Title: Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome
Abstract: Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case-control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984-3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2-78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95%CI = 1.8-217.2, p = 0.0006). MSH6*c.3959-3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984-3987dupGTCA and MSH6*c.3959-3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984-3987dupGTCA and MSH6*c.3959-3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients. © 2010 John Wiley & Sons A/S.
Keywords: adult; controlled study; aged; gene mutation; major clinical study; case control study; united states; endometrium cancer; genetic analysis; colorectal cancer; mutational analysis; haplotype; israel; founder effect; canada; ashkenazi jews; lynch syndrome; protein msh6; jew; hereditary nonpolyposis colorectal cancer; founder mutation; msh6
Journal Title: Clinical Genetics
Volume: 79
Issue: 6
ISSN: 0009-9163
Publisher: Wiley Blackwell  
Date Published: 2011-06-01
Start Page: 512
End Page: 522
Language: English
DOI: 10.1111/j.1399-0004.2010.01594.x
PROVIDER: scopus
PUBMED: 21155762
PMCID: PMC4541773
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-79955607652&partnerID=40&md5=e4a07b1394cdff13246fbca23cec1ba1
Notes: --- - "Export Date: 23 June 2011" - "CODEN: CLGNA" - "Source: Scopus"
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MSK Authors
  1. Douglas A Levine
    380 Levine
  2. Faina Bogomolniy
    50 Bogomolniy
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