TY - JOUR
T1 - Breast cancer risk genes - Association analysis in more than 113,000 women
AU - Breast Cancer Association Consortium
AU - Dorling, Leila
AU - Carvalho, Sara
AU - Allen, Jamie
AU - González-Neira, Anna
AU - Luccarini, Craig
AU - Wahlström, Cecilia
AU - Pooley, Karen A.
AU - Parsons, Michael T.
AU - Fortuno, Cristina
AU - Wang, Qin
AU - Bolla, Manjeet K.
AU - Dennis, Joe
AU - Keeman, Renske
AU - Alonso, M. Rosario
AU - Álvarez, Nuria
AU - Herraez, Belen
AU - Fernandez, Victoria
AU - Núñez-Torres, Rocio
AU - Osorio, Ana
AU - Valcich, Jeanette
AU - Li, Minerva
AU - Törngren, Therese
AU - Harrington, Patricia A.
AU - Baynes, Caroline
AU - Conroy, Don M.
AU - Decker, Brennan
AU - Fachal, Laura
AU - Mavaddat, Nasim
AU - Ahearn, Thomas
AU - Aittomäki, Kristiina
AU - Antonenkova, Natalia N.
AU - Arnold, Norbert
AU - Arveux, Patrick
AU - Ausems, Margreet G.E.M.
AU - Auvinen, Päivi
AU - Becher, Heiko
AU - Beckmann, Matthias W.
AU - Behrens, Sabine
AU - Bermisheva, Marina
AU - Białkowska, Katarzyna
AU - Blomqvist, Carl
AU - Bogdanova, Natalia V.
AU - Bogdanova-Markov, Nadja
AU - Bojesen, Stig E.
AU - Bonanni, Bernardo
AU - Børresen-Dale, Anne Lise
AU - Brauch, Hiltrud
AU - Briceno, Ignacio
AU - Gil, Fabian
AU - Torres, Diana
N1 - Publisher Copyright:
© 2021 Massachusetts Medical Society.
PY - 2021/2/4
Y1 - 2021/2/4
N2 - BACKGROUND 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. METHODS 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. RESULTS 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 variants. CONCLUSIONS 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.
AB - BACKGROUND 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. METHODS 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. RESULTS 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 variants. CONCLUSIONS 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.
UR - https://www.scopus.com/pages/publications/85100590625
U2 - 10.1056/NEJMoa1913948
DO - 10.1056/NEJMoa1913948
M3 - Article
C2 - 33471991
AN - SCOPUS:85100590625
SN - 0028-4793
VL - 384
SP - 428
EP - 439
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 5
ER -
SDG 3 Good Health and Well-being