Germline breast cancer susceptibility genes, tumor characteristics, and survival

Genome Medicine

Eldarina Azfar Wijaya¹  Mei Chee Tai¹  Soo-Hwang Teo²  Alison M. Dunning³  Douglas F. Easton⁴  Yirong Sim⁵  Veronique Kiak Mien Tan⁵  Benita Kiat-Tee Tan⁶  Patrick M. Y. Chan⁷  Juliana J. C. Chen⁷  Ern Yu Tan⁸  Soo Chin Lee⁹  Sue K. Park^1,10  Sung-Won Kim^1,11  Nur Aishah Mohd-Taib^1,12  Suniza Jamaris^1,12  Min Hyuk Lee^1,13  Shaik Ahmad Buhari^1,14  Ching Wan Chan^1,14  Jong Won Lee^1,15  Su-Ming Tan^1,16  Chi Wei Mok^1,16  Wai Peng Lee^1,16  Jaime Chin Mui Seah^1,16  Elaine Hsuen Lim^1,17  Marjanka K. Schmidt^1,18  Fuh Yong Wong^1,19  Alexis J. Khng^2,20  Hui Wen Loh^2,20  Jingmei Li^2,21  Peh Joo Ho^2,22  Geok Hoon Lim^2,23  Evan Woo^2,23  Swee Ho Lim^2,23  Joanne Ngeow^2,24  Mikael Hartman^2,25  Weang-Kee Ho^2,26  Cheng Har Yip^2,27 

[1] Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia;Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia;Department of Surgery, Faculty of Medicine, University of Malaya, Jalan Universiti, 50630, Kuala Lumpur, Malaysia;Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK;Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK;Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK;Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore;Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore;Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore;Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore;Department of General Surgery, Sengkang General Hospital, Singapore, Singapore;Department of General Surgery, Tan Tock Seng Hospital, 308433, Singapore, Singapore;Department of General Surgery, Tan Tock Seng Hospital, 308433, Singapore, Singapore;Lee Kong Chian School of Medicine, Singapore, Singapore;Institute of Molecular and Cell Biology, Singapore, Singapore;Department of Hematology-oncology, National University Cancer Institute, National University Health System, 119074, Singapore, Singapore;Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea;Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea;Cancer Research Institute, Seoul National University, Seoul, Republic of Korea;Department of Surgery, Breast Care Center, Daerim St. Mary’s Hospital, Seoul, Korea;Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia;UM Cancer Research Institute, Kuala Lumpur, Malaysia;Department of Surgery, Soonchunhyang University and Hospital, Seoul, Republic of Korea;Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore;Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea;Division of Breast Surgery, Changi General Hospital, Singapore, Singapore;Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore;Division of Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands;Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore;Genome Institute of Singapore, Human Genetics, Singapore, Singapore;Genome Institute of Singapore, Human Genetics, Singapore, Singapore;Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore;Genome Institute of Singapore, Human Genetics, Singapore, Singapore;Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore;KK Breast Department, KK Women’s and Children’s Hospital, 229899, Singapore, Singapore;Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore, Singapore;Cancer Genetics Service, National Cancer Centre Singapore, Singapore, Singapore;Oncology Academic Clinical Program, Duke NUS, Singapore, Singapore;Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore;Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore;Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore;School of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Jalan Broga, 43500, Semenyih, Selangor, Malaysia;Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia;Subang Jaya Medical Centre, Jalan SS 12/1A, 47500, Subang Jaya, Selangor, Malaysia;

关键词: Breast cancer;    Protein-truncating variants;    Overall survival;   

DOI  :  10.1186/s13073-021-00978-9

来源: Springer

【 摘 要 】

BackgroundMutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent.MethodsGene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease.ResultsPTV9genes carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35–5.17], moderately vs well-differentiated 2.33 [1.56–3.49]), as well as luminal B [HER−] and triple-negative subtypes (vs luminal A 2.15 [1.58–2.92] and 2.85 [2.17–3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2−] subtype remained significant after excluding BRCA1/2 carriers. PTV25genes carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV25genes carriership, but not PTV9genes carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16–2.28]).ConclusionsPTV9genes carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.

【 授权许可】

CC BY