Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Breast Cancer Association Consortium

OnderzoeksoutputAcademicpeer review

17 Citaten (Scopus)


Genetic testing for breast cancer susceptibility is widely used, but for many genes,
evidence of an association with breast cancer is weak, underlying risk estimates
are imprecise, and reliable subtype-specific risk estimates are lacking.
We used a panel of 34 putative susceptibility genes to perform sequencing on
samples from 60,466 women with breast cancer and 53,461 controls. In separate
analyses for protein-truncating variants and rare missense variants in these genes,
we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated
missense-variant associations according to domain and classification of pathogenicity.
Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2)
were associated with a risk of breast cancer overall with a P value of less than
0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D,
and TP53) were associated with a risk of breast cancer overall with a P value of
less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For
protein-truncating variants in 19 of the remaining 25 genes, the upper limit of
the 95% confidence interval of the odds ratio for breast cancer overall was less
than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were
higher for estrogen receptor (ER)–positive disease than for ER-negative disease;
for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and
RAD51D, odds ratios were higher for ER-negative disease than for ER-positive
disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were
associated with a risk of breast cancer overall with a P value of less than 0.001.
For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk
of breast cancer overall, with the risk being similar to that of protein-truncating
The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates
of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)
Originele taal-2English
Pagina's (van-tot)428-439
TijdschriftNew England Journal of Medicine
Nummer van het tijdschrift5
StatusPublished - 4-feb-2021

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