title: Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts.
abstract: The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a population-based case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically- and geographically-selected populations.
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, MA, USA. belldaph@mail.nih.gov
authors.forename: Daphne W
authors.initials: DW
authors.lastname: Bell
authors.forename: Sang H
authors.initials: SH
authors.lastname: Kim
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Taryn A
authors.initials: TA
authors.lastname: Schiripo
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Harris
authors.forename: Sara M
authors.initials: SM
authors.lastname: Haserlat
authors.forename: Doke C R
authors.initials: DC
authors.lastname: Wahrer
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Mary B
authors.initials: MB
authors.lastname: Daly
authors.forename: Kristin B
authors.initials: KB
authors.lastname: Niendorf
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Smith
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D017668:Age of Onset; D000368:Aged; D044466:Asian People / Q000235:genetics; D001943:Breast Neoplasms / Q000208:ethnology* / Q000235:genetics*; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006254:Hawaii / Q000208:ethnology; D006630:Hispanic or Latino / Q000235:genetics; D006639:Histidine; D006801:Humans; D007532:Isoleucine; D007930:Leucine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D011237:Predictive Value of Tests; D011392:Proline; D011471:Prostatic Neoplasms / Q000208:ethnology* / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D013912:Threonine; D014443:Tyrosine; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D007532:Isoleucine; D013912:Threonine; D014443:Tyrosine; D006639:Histidine; D011392:Proline; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D007930:Leucine