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Germline breast cancer susceptibility genes, tumor characteristics, and survival

Ho PJ 1 , Khng AJ 1 , Loh HW 1 , Ho WK 2 , Yip CH 3 , Mohd-Taib NA 4 Show all authors , Tan VKM 5 , Tan BK 5 , Tan SM 6 , Tan EY 7 , Lim SH 8 , Jamaris S 4 , Sim Y 5 , Wong FY 9 , Ngeow J 10 , Lim EH 11 , Tai MC 12 , Wijaya EA 12 , Lee SC 13 , Chan CW 14 , Buhari SA 14 , Chan PMY 7 , Chen JJC 7 , Seah JCM 6 , Lee WP 6 , Mok CW 6 , Lim GH 8 , Woo E 8 , Kim SW 15 , Lee JW 16 , Lee MH 17 , Park SK 18 , Dunning AM 19 , Easton DF 19 , Schmidt MK 20 , Teo SH 12 , Li J 21 , Hartman M 22

Affiliations 

  • 1 Genome Institute of Singapore, Human Genetics, Singapore, Singapore
  • 2 School of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia, Jalan Broga, 43500, Semenyih, Selangor, Malaysia
  • 3 Subang Jaya Medical Centre, Jalan SS 12/1A, 47500, Subang Jaya, Selangor, Malaysia
  • 4 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 5 Department of Breast Surgery, Singapore General Hospital, Singapore, Singapore
  • 6 Division of Breast Surgery, Changi General Hospital, Singapore, Singapore
  • 7 Department of General Surgery, Tan Tock Seng Hospital, Singapore, 308433, Singapore
  • 8 KK Breast Department, KK Women's and Children's Hospital, Singapore, 229899, Singapore
  • 9 Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore
  • 10 Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore, Singapore
  • 11 Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
  • 12 Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia
  • 13 Department of Hematology-oncology, National University Cancer Institute, National University Health System, Singapore, 119074, Singapore
  • 14 Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore
  • 15 Department of Surgery, Breast Care Center, Daerim St. Mary's Hospital, Seoul, Korea
  • 16 Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
  • 17 Department of Surgery, Soonchunhyang University and Hospital, Seoul, Republic of Korea
  • 18 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
  • 19 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 20 Division of Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
  • 21 Genome Institute of Singapore, Human Genetics, Singapore, Singapore. lijm1@gis.a-star.edu.sg
  • 22 Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
Genome Med, 2021 Dec 02;13(1):185.
PMID: 34857041 DOI: 10.1186/s13073-021-00978-9

Abstract

BACKGROUND: Mutations 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.

METHODS: Gene 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.

RESULTS: PTV9genes 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]).

CONCLUSIONS: PTV9genes 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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