Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer

Human Genomics

Research

Soo-Chin Lee¹  Melissa Hum²  Ning-Yuan Lee²  Matthew K. Myint²  Sabna Zihara²  Ann S. G. Lee³  Chee-Keong Toh⁴  Lanying Wang⁴  Eng-Huat Tan⁵  Yoon-Sim Yap⁶  Darren Wan-Teck Lim⁶  Gillianne G. Y. Lai⁶  Daniel S. W. Tan⁷  Anders Skanderup⁸  Min-Han Tan⁹  Jens Samol^1,10  Peter Ang^1,11 

[1] Department of Hematology-Oncology, National University Cancer Institute, Singapore (NCIS), National University Health System, 5 Lower Kent Ridge Road, 119074, Singapore, Singapore;Cancer Science Institute, Singapore (CSI), National University of Singapore, 14 Medical Dr, 117599, Singapore, Singapore;Division of Cellular and Molecular Research, National Cancer Centre Singapore, 30 Hospital Boulevard, 168583, Singapore, Singapore;Division of Cellular and Molecular Research, National Cancer Centre Singapore, 30 Hospital Boulevard, 168583, Singapore, Singapore;SingHealth Duke-NUS Oncology Academic Clinical Programme (ONCO ACP), Duke-NUS Medical School, 8 College Road, 169857, Singapore, Singapore;Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, 117593, Singapore, Singapore;Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, 168583, Singapore, Singapore;Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, 168583, Singapore, Singapore;Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, 30 Hospital Boulevard, 168583, Singapore, Singapore;Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, 168583, Singapore, Singapore;SingHealth Duke-NUS Oncology Academic Clinical Programme (ONCO ACP), Duke-NUS Medical School, 8 College Road, 169857, Singapore, Singapore;Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, 168583, Singapore, Singapore;SingHealth Duke-NUS Oncology Academic Clinical Programme (ONCO ACP), Duke-NUS Medical School, 8 College Road, 169857, Singapore, Singapore;Genome Institute of Singapore, 60 Biopolis St, 138672, Singapore, Singapore;Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, 30 Hospital Boulevard, 168583, Singapore, Singapore;Genome Institute of Singapore, 60 Biopolis St, 138672, Singapore, Singapore;Lucence Diagnostics Pte Ltd, 211 Henderson Road, 159552, Singapore, Singapore;Medical Oncology Department, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, 308433, Singapore, Singapore;Johns Hopkins University, 21218, Baltimore, MD, USA;Oncocare Cancer Centre, Gleneagles Medical Centre, 6 Napier Road, 258499, Singapore, Singapore;

关键词: Multiple primary cancers;    Breast cancer;    Lung cancer;    Whole-exome sequencing;    Germline variants;   

DOI  :  10.1186/s40246-023-00510-7

 received in 2023-05-10, accepted in 2023-07-10,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundCancer predisposition is most often studied in the context of single cancers. However, inherited cancer predispositions can also give rise to multiple primary cancers. Yet, there is a paucity of studies on genetic predisposition in multiple primary cancers, especially those outside of well-defined cancer predisposition syndromes. This study aimed to identify germline variants associated with dual primary cancers of the breast and lung.MethodsExome sequencing was performed on germline DNA from 55 Singapore patients (52 [95%] never-smokers) with dual primaries in the breast and lung, confirmed by histopathology. Using two large control cohorts: the local SG10K_Health (n = 9770) and gnomAD non-cancer East Asians (n = 9626); and two additional local case cohorts of early-onset or familial breast cancer (n = 290), and lung cancer (n = 209), variants were assessed for pathogenicity in accordance with ACMG/AMP guidelines. In particular, comparisons were made with known pathogenic or likely pathogenic variants in the ClinVar database, pathogenicity predictions were obtained from in silico prediction software, and case–control association analyses were performed.ResultsAltogether, we identified 19 pathogenic or likely pathogenic variants from 16 genes, detected in 17 of 55 (31%) patients. Six of the 19 variants were identified using ClinVar, while 13 variants were classified pathogenic or likely pathogenic using ACMG/AMP guidelines. The 16 genes include well-known cancer predisposition genes such as BRCA2, TP53, and RAD51D; but also lesser known cancer genes EXT2, WWOX, GATA2, and GPC3. Most of these genes are involved in DNA damage repair, reaffirming the role of impaired DNA repair mechanisms in the development of multiple malignancies. These variants warrant further investigations in additional populations.ConclusionsWe have identified both known and novel variants significantly enriched in patients with primary breast and lung malignancies, expanding the body of known cancer predisposition variants for both breast and lung cancer. These variants are mostly from genes involved in DNA repair, affirming the role of impaired DNA repair in the predisposition and development of multiple cancers.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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