title: MSH2 c.1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese population.
abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2% of all colorectal cancer (CRC) cases and is the most common hereditary CRC syndrome. We have previously reported a high incidence of microsatellite instability (MSI) and germline mismatch repair (MMR) gene mutations in young Hong Kong Chinese with CRC. Ongoing studies at the Hereditary Gastrointestinal Cancer Registry in Hong Kong have revealed a unique germline MSH2 c.1452-1455delAATG mutation that has not been reported in other ethnic groups. Detailed analysis showed that this specific MSH2 mutation constituted 21% of all germline MMR gene mutations and 36% of all MSH2 germline mutations identified. We designed a specific PCR-based diagnostic test on paraffin-embedded tissues and identified this germline mutation in 2 (1.5%) of 138 consecutive patients with early-onset CRC (<46 years of age at diagnosis). Haplotype analysis was performed using 11 microsatellite markers located between D2S391 and D2S123. All 10 families had the same disease haplotype, suggesting a founder effect. These 10 families all originated from the Chinese province of Guangdong, which historically included Hong Kong. It is the most populous of the Chinese provinces, with a population of >93 million. Further analysis suggested that this founder mutation may date back to between 22 and 103 generations ago. The identification of this MSH2 founder mutation has important implications for the design of mutation-detection strategies for the southern Chinese population. Since there were major emigrations from Hong Kong and Guangdong province during the 19th and 20th centuries, this finding is also significant for Chinese communities worldwide.
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Tsun Leung
authors.initials: TL
authors.lastname: Chan
authors.forename: Yee Wai
authors.initials: YW
authors.lastname: Chan
authors.forename: Judy W C
authors.initials: JW
authors.lastname: Ho
authors.forename: Celine
authors.initials: C
authors.lastname: Chan
authors.forename: Annie S Y
authors.initials: AS
authors.lastname: Chan
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Polly W Y
authors.initials: PW
authors.lastname: Lam
authors.forename: Chun Wah
authors.initials: CW
authors.lastname: Tse
authors.forename: Kam Cheong
authors.initials: KC
authors.lastname: Lee
authors.forename: Chi Waii
authors.initials: CW
authors.lastname: Lau
authors.forename: Elaine
authors.initials: E
authors.lastname: Gwi
authors.forename: Suet Yi
authors.initials: SY
authors.lastname: Leung
authors.forename: Siu Tsan
authors.initials: ST
authors.lastname: Yuen
mesh_terms: D002681:China / Q000453:epidemiology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000208:ethnology / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D051718:MutS Homolog 2 Protein; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein