title: Association of rare MSH6 variants with familial breast cancer.
abstract: Germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 predispose to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer). Recently, we have shown that the CHEK2 1100delC mutation also is associated with Lynch syndrome/Lynch syndrome-associated families albeit in a polygenic setting. Two of the ten CHEK2 1100delC positive Lynch syndrome families additionally carried a pathogenic MLH1 or MSH6 mutation, suggesting that mutations in mismatch repair genes may be involved in CHEK2 1100delC-associated cancer phenotypes. A phenotype of importance is hereditary breast and colorectal cancer (HBCC), with the CHEK2 1100delC mutation present in almost one-fifth of the families-again in a polygenic setting. In order to evaluate the involvement of MSH6 in polygenic CHEK2 cancer susceptibility, we, here, have analyzed the entire MSH6 coding sequence for genetic alterations in 68 HBCC breast cancer families. Rare MSH6 variants, with population frequencies below 1%, were identified in 11.8% of HBCC breast cancer families, whereas the same variants were identified in only 1.5% of population controls, suggesting that rare MSH6 variants are associated with HBCC breast cancer (P < or = 0.00001). However, screening of the entire MSH6 coding sequence in 68 non-HBCC breast cancer families showed a similar association (8.8 vs. approximately 1.4% in controls, P < or = 0.001), suggesting that rare MSH6 variants are not confined to HBCC breast cancer. Together, our data suggest that rare MSH6 variants may predispose to familial breast cancer. However, none of the rare MSH6 variants are obviously pathogenic, suggesting that a more subtle disease mechanism may operate in breast carcinogenesis.
authors.affiliation: Department of Medical Oncology, Josephine Nefkens Institute Be414, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Marijke
authors.initials: M
authors.lastname: Wasielewski
authors.forename: Muhammad
authors.initials: M
authors.lastname: Riaz
authors.forename: Joyce
authors.initials: J
authors.lastname: Vermeulen
authors.forename: Ans
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: Ineke
authors.initials: I
authors.lastname: Labrijn-Marks
authors.forename: Renske
authors.initials: R
authors.lastname: Olmer
authors.forename: Linda
authors.initials: L
authors.lastname: van der Spaa
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
authors.forename: Mieke
authors.initials: M
authors.lastname: Schutte
mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007438:Introns; D008875:Middle Aged; D020412:Multifactorial Inheritance; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D010375:Pedigree; D010641:Phenotype; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein