Shimelis, Hermela
Mayo Clinic
Mayo Clinic, Rochester, Minnesota.
Citations 2
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.
Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer
Kiiski, Johanna I. , Pelttari, Liisa M. , Khan, Sofia , Freysteinsdóttir, Edda Sigríður, Reynisdóttir, Inga , Hart, Steven N. , Shimelis, Hermela , Vilske, Sara, Kallioniemi, Anne , Schleutker, Johanna , Leminen, Arto , Blomqvist, Carl , Barkardóttir, Rósa B. , Aittomäki, Kristiina , Nevanlinna, Heli , Bützow, Ralf C. , Couch, Fergus J. , Pelttari, L M , Nevanlinna, H , Schleutker, Johanna , Hart, Steven N , Shimelis, Hermela
Proceedings of the National Academy of Sciences | October 6, 2014 | Volume: 111 | Issue: 42 | Pages: 15172-15177
Significance The major portion of hereditary breast cancer still remains unexplained, and many susceptibility loci are yet to be found. Exome sequencing of 24 high-risk familial BRCA1/2 -negative breast cancer patients and further genotyping of a large sample set of breast/ovarian cancer cases and controls was used to discover previously unidentified susceptibility alleles and genes. A significant association of a FANCM nonsense mutation with breast cancer, especially triple-negative breast cancer, identifies FANCM as a breast cancer susceptibility gene. Identification of such risk alleles is expected to improve cancer risk assessment for breast cancer patients and families, and may lead to improvements in the prevention, early diagnosis, and treatment of cancer.