Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study.
BACKGROUND
Both protein-truncating variants and some missense substitutions in CHEK2 confer increased risk of breast cancer. However, no large-scale study has used full open reading frame mutation screening to assess the contribution of rare missense substitutions in CHEK2 to breast cancer risk. This absence has been due in part to a lack of validated statistical methods for summarizing risk attributable to large numbers of individually rare missense substitutions.


METHODS
Previously, we adapted an in silico assessment of missense substitutions used for analysis of unclassified missense substitutions in BRCA1 and BRCA2 to the problem of assessing candidate genes using rare missense substitution data observed in case-control mutation-screening studies. The method involves stratifying rare missense substitutions observed in cases and/or controls into a series of grades ordered a priori from least to most likely to be evolutionarily deleterious, followed by a logistic regression test for trends to compare the frequency distributions of the graded missense substitutions in cases versus controls. Here we used this approach to analyze CHEK2 mutation-screening data from a population-based series of 1,303 female breast cancer patients and 1,109 unaffected female controls.


RESULTS
We found evidence of risk associated with rare, evolutionarily unlikely CHEK2 missense substitutions. Additional findings were that (1) the risk estimate for the most severe grade of CHEK2 missense substitutions (denoted C65) is approximately equivalent to that of CHEK2 protein-truncating variants; (2) the population attributable fraction and the familial relative risk explained by the pool of rare missense substitutions were similar to those explained by the pool of protein-truncating variants; and (3) post hoc power calculations implied that scaling up case-control mutation screening to examine entire biochemical pathways would require roughly 2,000 cases and controls to achieve acceptable statistical power.


CONCLUSIONS
This study shows that CHEK2 harbors many rare sequence variants that confer increased risk of breast cancer and that a substantial proportion of these are missense substitutions. The study validates our analytic approach to rare missense substitutions and provides a method to combine data from protein-truncating variants and rare missense substitutions into a one degree of freedom per gene test.
International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon CEDEX 08, F-69372, France.
Florence
F
Le Calvez-Kelm
Fabienne
F
Lesueur
Francesca
F
Damiola
Maxime
M
Vallée
Catherine
C
Voegele
Davit
D
Babikyan
Geoffroy
G
Durand
Nathalie
N
Forey
Sandrine
S
McKay-Chopin
Nivonirina
N
Robinot
Tù
T
Nguyen-Dumont
Alun
A
Thomas
Graham B
GB
Byrnes
John L
JL
Hopper
Melissa C
MC
Southey
Irene L
IL
Andrulis
Esther M
EM
John
Sean V
SV
Tavtigian
D000328:Adult; D019943:Amino Acid Substitution; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense; D012042:Registries; D055815:Young Adult
D064447:Checkpoint Kinase 2
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