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. 2023 Jul 17;17(1):66.
doi: 10.1186/s40246-023-00510-7.

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

Ning-Yuan Lee  1 , Melissa Hum  1 , Sabna Zihara  1 , Lanying Wang  2 , Matthew K Myint  1 , Darren Wan-Teck Lim  2   3 , Chee-Keong Toh  2 , Anders Skanderup  4 , Jens Samol  5   6 , Min-Han Tan  7 , Peter Ang  8 , Soo-Chin Lee  9   10 , Eng-Huat Tan  2   11 , Gillianne G Y Lai  2   3 , Daniel S W Tan  2   3   4   11 , Yoon-Sim Yap  2   3 , Ann S G Lee  12   13   14
Affiliations

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

Ning-Yuan Lee et al. Hum Genomics. .

Erratum in

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.

Keywords: Breast cancer; Germline variants; Lung cancer; Multiple primary cancers; Whole-exome sequencing.

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Conflict of interest statement

P.A. reports receiving travel support and/or honoraria from AstraZeneca, DKSH, Eisai, Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche, and MSD, all of which are outside the submitted work. M.-H.T. reports being a director, shareholder, and Chief Executive Officer of Lucence, outside of the submitted work. S.-C.L. reports grant support/research collaborations with Pfizer, Eisai, Taiho, ACT Genomics, Bayer, and MSD; advisory board/speaker invitations from Pfizer, Novartis, Astra Zeneca, ACT Genomics, Eli Lilly, MSD, Roche, Eisai and Daiichi-Sankyo; conference support from Amgen, Pfizer and Roche, all of which are outside the submitted work. No other disclosures were reported.

Figures

Fig. 1
Fig. 1
Overview of the study design
Fig. 2
Fig. 2
ClinVar-recorded pathogenic or likely pathogenic variants found in 55 patients with dual breast and lung cancer
See this image and copyright information in PMC

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