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Title: Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer
Authors: Lee, Ning-Yuan
Hum, Melissa 
Zihara, Sabna
Wang, Lanying
Myint, Matthew K 
Lim, Darren Wan-Teck 
Toh, Chee-Keong 
Skanderup, Anders 
Samol, Jens
Tan, Min-Han 
Ang, Peter
Lee, Soo-Chin 
Tan, Eng-Huat 
Lai, Gillianne GY 
Tan, Daniel SW 
Yap, Yoon-Sim 
Lee, Ann SG 
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Multiple primary cancers
Breast cancer
Lung cancer
Whole-exome sequencing
Germline variants
Issue Date: 17-Jul-2023
Publisher: BMC
Citation: Lee, Ning-Yuan, Hum, Melissa, Zihara, Sabna, Wang, Lanying, Myint, Matthew K, Lim, Darren Wan-Teck, Toh, Chee-Keong, Skanderup, Anders, Samol, Jens, Tan, Min-Han, Ang, Peter, Lee, Soo-Chin, Tan, Eng-Huat, Lai, Gillianne GY, Tan, Daniel SW, Yap, Yoon-Sim, Lee, Ann SG (2023-07-17). Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer. HUMAN GENOMICS 17 (1). ScholarBank@NUS Repository.
Abstract: Background: Cancer 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. Methods: Exome 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. Results: Altogether, 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. Conclusions: We 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.
ISSN: 1473-9542
DOI: 10.1186/s40246-023-00510-7
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