title: Cancer risks and immunohistochemical profiles linked to the Danish MLH1 Lynch syndrome founder mutation.
abstract: Founder mutations with a large impact in distinct populations have been described in Lynch syndrome. In Denmark, the MLH1 c.1667+2_1667_+8TAAATCAdelinsATTT mutation accounts for 25 % of the MLH1 mutant families. We used the national Danish hereditary nonpolyposis colorectal cancer register to estimate the cumulative lifetime risks for Lynch syndrome-associated cancer in 16 founder mutation families with comparison to 47 other MLH1 mutant families. The founder mutation conferred comparable risks for colorectal cancer (relative risks, RR, of 0.99 for males and 0.79 for females) and lower risks for extracolonic cancer (RR of 0.69 for endometrial cancer and 0.39 for all other extracolonic cancers). We also characterized expression of key Wnt-signaling proteins in colorectal cancers with the founder mutation. Aberrant staining affected β-catenin in 59 %, E-cadherin in 68 %, TCF-4 in 94 % and Cyclin D1 in 68 % with extensive inter-tumor variability despite the same underlying germline mutation. In conclusion, the Danish MLH1 founder mutation that accounts for a significant proportion of Lynch syndrome and is associated with a lower risk for extracolonic cancers.
authors.affiliation: HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Kettegård Alle 30, Hvidovre, Denmark. 2xtherkild@gmail.com
authors.forename: Christina
authors.initials: C
authors.lastname: Therkildsen
authors.forename: Anna
authors.initials: A
authors.lastname: Isinger-Ekstrand
authors.forename: Steen
authors.initials: S
authors.lastname: Ladelund
authors.forename: Anja
authors.initials: A
authors.lastname: Nissen
authors.forename: Eva
authors.initials: E
authors.lastname: Rambech
authors.forename: Inge
authors.initials: I
authors.lastname: Bernstein
authors.forename: Mef
authors.initials: M
authors.lastname: Nilbert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications* / Q000235:genetics; D003718:Denmark / Q000453:epidemiology; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D060449:Wnt Signaling Pathway; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1