Citations 3
Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
Nagaraj, Anil Belur , Shimelis, Hermela , Montalban, Gemma , Lee, Kun Y. , Huang, Huaizhi , Lumby, Carolyn A. , Na, Jie , Susswein, Lisa R. , Marshall, Megan L. , Hiraki, Susan , LaDuca, Holly , Yussuf, Amal , Pesaran, Tina , Haiman, Christopher A. , Lindström, Sara , Vachon, Celine M. , Ong, Irene M. , Nathanson, Katherine L. , Mer, Georges , Yadav, Siddhartha , Hruska, Kathleen S. , Dolinsky, Jill S. , Weroha, S. John , Simard, Jacques , Pang, Yuan‐Ping , Chen, Chen , Hu, Chunling , Nagaraj, Anil Belur , Shimelis, Hermela , Montalban, Gemma , Lee, Kun Y , Huang, Huaizhi , Lumby, Carolyn A , Na, Jie , Susswein, Lisa R , Roberts, Maegan E , Marshall, Megan L , Hiraki, Susan , LaDuca, Holly , Chao, Elizabeth , Yussuf, Amal , Pesaran, Tina , Neuhausen, Susan L. , Haiman, Christopher A , Kraft, Peter , Lindstrom, Sara , Palmer, Julie R , Teras, Lauren R , Vachon, Celine M. , Yao, Song , Ong, Irene M , Nathanson, Katherine L , Weitzel, Jeffrey N , Boddicker, Nicholas J , Gnanaolivu, Rohan , Polley, Eric C , Mer, Georges , Cui, Gaofeng , Karam, Rachid , Richardson, Marcy E , Domchek, Susan M , Yadav, Siddhartha , Hruska, Kathleen S , Dolinsky, Jill S , Weroha, S John , Hart, Steven N , Simard, Jacques , Masson, Jean Yves , Pang, Yuan-Ping , Couch, Fergus J. , Chen, C , Hu, Chunling , Roberts, Maegan E. , Kraft, Peter , Palmer, Julie R. , Teras, Lauren R. , Yao, Song , Weitzel, Jeffrey N. , Boddicker, Nicholas , Gnanaolivu, Rohan , Polley, Eric C. , Cui, Gaofeng , Karam, Rachid , Domchek, Susan M. , Hart, Steven N. , Masson, Jean‐Yves , Couch, Fergus J.
Cancer Research | May 30, 2023 | Volume: 83 | Issue: 15 | Pages: 2557-2571
Abstract Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C−/− cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.
Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast
Yadav, Siddhartha , Nathanson, Katherine L. , Weitzel, Jeffrey N. , Goldgar, David E. , Kraft, Peter , Gnanaolivu, Rohan D., Na, Jie , Huang, Hongyan, Boddicker, Nicholas , Larson, Nicole, Gao, Chi , Weinberg, Clarice, Vachon, Celine M. , Taylor, Jack A. , Patel, Alpa, Olson, Janet E., Lindstrom, Sara, Lacey, James V., Kurian, Allison W. , John, Esther M. , Haiman, Christopher, Auer, Paul W., Anton-Culver, Hoda, Chao, Elizabeth, Yussuf, Amal , Pesaran, Tina , Dolinsky, Jill S. , LaDuca, Holly , Hu, Chunling , Nathanson, Katherine L , Weitzel, Jeffrey N , Goldgar, David E , Kraft, Peter , Na, Jie , Boddicker, Nicholas J , Gao, Chi , Yao, Song , Vachon, Celine M. , Trentham-Dietz, Amy , Taylor, Jack A , Sandler, Dale P , Palmer, Julie R , Neuhausen, Susan L. , Martı́nez, Marı́a Elena , Kurian, Allison W , John, Esther M , Bernstein, Leslie , Ambrosone, Christine B , Karam, Rachid , Yussuf, Amal , Pesaran, Tina , Dolinsky, Jill S , Hart, Steven N , LaDuca, Holly , Polley, Eric C , Domchek, Susan M , Couch, Fergus J. , Yadav, Siddhartha , Gnanaolivu, Rohan D., Huang, Hongyan, Larson, Nicole, Weinberg, Clarice, Patel, Alpa, Olson, Janet E., Lindstrom, Sara, Lacey, James V., Haiman, Christopher, Auer, Paul W., Anton-Culver, Hoda, Chao, Elizabeth
Journal of Clinical Oncology | October 21, 2021 | Volume: 39 | Issue: 35 | Pages: 3918-3926
PURPOSETo determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.MATERIALS AND METHODSThe 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).RESULTSThe 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.CONCLUSIONThe 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.
Risk of Late-Onset Breast Cancer in Genetically Predisposed Women
Boddicker, Nicholas , Weitzel, Jeffrey N. , Kraft, Peter , Nathanson, Katherine L. , Goldgar, David E. , Na, Jie , Huang, Hongyan , Larson, Nicole L. , Yussuf, Amal , Vachon, Celine M. , Taylor, Jack A. , Scott, Christopher E., Pesaran, Tina , Patel, Alpa V. , Ong, Irene M. , Martínez, Elena, Ma, Huiyan , Lindström, Sara , Hodge, James M. , Haiman, Christopher A. , Gaudet, Mia M. , Gao, Chi , LaDuca, Holly , Dolinsky, Jill S. , Carter, Brian D., Auer, Paul, Yadav, Siddhartha , Chen, Chen , Boddicker, Nicholas J , Hu, Chunling , Weitzel, Jeffrey N , Kraft, Peter , Nathanson, Katherine L , Goldgar, David E , Na, Jie , Gnanaolivu, Rohan D., Yussuf, Amal , Yao, Song , Vachon, Celine M. , Trentham-Dietz, Amy , Teras, Lauren R , Taylor, Jack A , Sandler, Dale P , Pesaran, Tina , Palmer, Julie R , Ong, Irene M , Neuhausen, Susan L. , Martı́nez, Marı́a Elena , Karam, Rachid , Hodge, James M , Gaudet, Mia M , Gao, Chi , LaDuca, Holly , Dolinsky, Jill S , Burnside, Elizabeth S , Bertrand, Kimberly A , Bernstein, Leslie , Ambrosone, Christine B , Yadav, Siddhartha , Hart, Steven N , Polley, Eric C , Domchek, Susan M , Couch, Fergus J. , Chen, C , Hu, Chunling , Gnanaolivu, Rohan , Yao, Song , Trentham‐Dietz, Amy , Teras, Lauren R. , Sandler, Dale P. , Palmer, Julie R. , Olson, Janet E. , O’Brien, Katie M. , Marchand, Loı̈c Le , Kooperberg, Charles , Karam, Rachid , Hunter, David J. , Lacey, James V. , Chao, Elizabeth , Burnside, Elizabeth S. , Bertrand, Kimberly A. , Bernstein, Leslie , Ambrosone, Christine B. , Hart, Steven N. , Polley, Eric C. , Domchek, Susan M. , Couch, Fergus J.
Journal of Clinical Oncology | July 22, 2021 | Volume: 39 | Issue: 31 | Pages: 3430-3440
PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.