TY - JOUR
T1 - Germline Pathogenic Variants in Cancer Predisposition Genes among Women with Invasive Lobular Carcinoma of the Breast
AU - Yadav, Siddhartha
AU - Hu, Chunling
AU - Nathanson, Katherine L.
AU - Weitzel, Jeffrey N.
AU - Goldgar, David E.
AU - Kraft, Peter
AU - Gnanaolivu, Rohan D.
AU - Na, Jie
AU - Huang, Hongyan
AU - Boddicker, Nicholas J.
AU - Larson, Nicole
AU - Gaoc, Chi
AU - Yao, Song
AU - Weinberg, Clarice
AU - Vachon, Celine M.
AU - Trentham-Dietz, Amy
AU - Taylor, Jack A.
AU - Sandler, Dale R.
AU - Patel, Alpa
AU - Palmer, Julie R.
AU - Olson, Janet E.
AU - Neuhausen, Susan
AU - Martinez, Elena
AU - Lindstrom, Sara
AU - Lacey, James V.
AU - Kurian, Allison W.
AU - John, Esther M.
AU - Haiman, Christopher
AU - Bernstein, Leslie
AU - Auer, Paul W.
AU - Anton-Culver, Hoda
AU - Ambrosone, Christine B.
AU - Karam, Rachid
AU - Chao, Elizabeth
AU - Yussuf, Amal
AU - Pesaran, Tina
AU - Dolinsky, Jill S.
AU - Hart, Steven N.
AU - LaDuca, Holly
AU - Polley, Eric C.
AU - Domchek, Susan M.
AU - Couch, Fergus J.
N1 - Funding Information:
Cancer Research Foundation. Additional support for the contributing studies was provided by NIH awards U01CA164974, R01CA098663, R01CA100598, R01CA185623, P01CA151135, R01CA097396, P30CA16056, U01CA164973, U01CA164920, R01CA204819, R01CA077398, U01CA199277, P30CA014520, P30CA033572, P30CA023100, U01CA82004, R01CA047147, R01CA067264, UM1CA186107, UM1CA164917, P01CA87969, R01CA49449, R01CA58860, R01CA92044, U01CA176726, and R01CA67262; NHLBI contracts (HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C); NIEHS intramural awards (Z01-ES044005, Z01-ES049033, and Z01-ES102245); American Cancer Society; Susan G. Komen for the Cure (J.R.P., S.M.D., and 2SISTER); Breast Cancer Research Foundation (F.J.C., C.B.A., J.N.W., S.M.D., and K.L.N.); Karin Grunebaum Cancer Research Foundation (J.R.P.); the University of Wisconsin-Madison Office of the Vice Chancellor for Research and Graduate Education (A.T.D.); The California Breast Cancer Research Fund (contract 97-10500); California Department of Public Health; and The Lon V Smith Foundation (LVS39420).
Funding Information:
Supported by NIH grants R01CA192393, R01CA225662, and R35CA253187, an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer [P50CA116201], and a grant from Breast
Publisher Copyright:
© 2021 by American Society of Clinical Oncology.
PY - 2021/12/10
Y1 - 2021/12/10
N2 - PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] . 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR , 2) of ILC. Compared with IDC, CDH1 PVs were . 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.
AB - PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] . 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR , 2) of ILC. Compared with IDC, CDH1 PVs were . 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.
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U2 - 10.1200/JCO.21.00640
DO - 10.1200/JCO.21.00640
M3 - Article
C2 - 34672684
AN - SCOPUS:85121816355
SN - 0732-183X
VL - 39
SP - 3918
EP - 3926
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 35
ER -