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. 2022 Jul 1;31(7):1450-1459.
doi: 10.1158/1055-9965.EPI-21-1287.

Germline Pathogenic Variants Impact Clinicopathology of Advanced Lung Cancer

Semanti Mukherjee  1   2 , Chaitanya Bandlamudi  3 , Matthew D Hellmann  1 , Yelena Kemel  4 , Esther Drill  5 , Hira Rizvi  1 , Kaitlyn Tkachuk  1 , Aliya Khurram  1 , Michael F Walsh  1   2 , Marjorie G Zauderer  1   2 , Diana Mandelker  6 , Sabine Topka  1   7 , Ahmet Zehir  6 , Preethi Srinivasan  3 , Myvizhi Esai Selvan  8   9   10 , Maria I Carlo  1   2 , Karen A Cadoo  1   2 , Alicia Latham  1   2 , Jada G Hamilton  1   11 , Ying L Liu  1   2 , Steven M Lipkin  2 , Sami Belhadj  1 , Gareth L Bond  12 , Zeynep H Gümüş  8   9   10 , Robert J Klein  8 , Marc Ladanyi  6 , David B Solit  1   2   3 , Mark E Robson  1   2 , David R Jones  1 , Mark G Kris  1 , Joseph Vijai  1   2   7 , Zsofia K Stadler  1   2 , Christopher I Amos  12 , Barry S Taylor  3   5   13 , Michael F Berger  3   14   13 , Charles M Rudin  1   2   15 , Kenneth Offit  1   2   6
Affiliations

Germline Pathogenic Variants Impact Clinicopathology of Advanced Lung Cancer

Semanti Mukherjee et al. Cancer Epidemiol Biomarkers Prev. .

Abstract

Background: The genetic factors that modulate risk for developing lung cancer have not been fully defined. Here, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic variants (PV) in patients with advanced lung cancer.

Methods: We studied clinical and tumor characteristics of germline PV in 5,118 patients who underwent prospective genomic profiling using paired tumor-normal tissue samples in 468 cancer genes.

Results: Germline PV in high/moderate-penetrance genes were observed in 222 (4.3%) patients; of these, 193 patients had PV in DNA damage repair (DDR) pathway genes including BRCA2 (n = 54), CHEK2 (n = 30), and ATM (n = 26) that showed high rate of biallelic inactivation in tumors. BRCA2 heterozygotes with lung adenocarcinoma were more likely to be never smokers and had improved survival compared with noncarriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1, and MEN1) were diagnosed at younger age compared with noncarriers, and of tumor suppressors, 75% demonstrated biallelic inactivation in tumors. A significantly higher proportion of germline PV in high/moderate-penetrance genes were detected in high-risk patients who had either a family history of any cancer, multiple primary tumors, or early age at diagnosis compared with unselected patients (10.5% vs. 4.1%; P = 1.7e-04).

Conclusions: These data underscore the biological and clinical importance of germline mutations in highly penetrant DDR genes as a risk factor for lung cancer.

Impact: The family members of lung cancer patients harboring PV in cancer predisposing genes should be referred for genetic counseling and may benefit from proactive surveillance.

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Figures

Figure 1:
Figure 1:
Distribution germline PV in 5118 lung cancer patients. a) The relative frequencies of germline PV in genes classified by penetrance; b) Number of patients carrying germline PV in lung cancer predisposing genes or high/moderate penetrance genes and diagnosed with Lung Adenocarcinoma (LUAD), Lung Squamous Cell Carcinoma (LUSQ), Small Cell Lung Cancer (SCLC) and Other Subtypes.
Figure 2:
Figure 2:
Distribution of biallelic inactivation in patients with germline PV. a) Biallelic inactivation rate in patients with lung adenocarcinoma; b) Biallelic inactivation rate in patients with germline PV compared to biallelic inactivation rate in patients harboring benign/likely benign variants in the same genes; c) Biallelic inactivation rate in patients with lung squamous cell carcinoma
Figure 3.
Figure 3.
Association of germline PV with clinical characteristics in lung adenocarcinoma patients. a) Association with age of cancer diagnosis; b) Association with smoking history (never-smoker vs current/former smokers)
Figure 4:
Figure 4:
Overall survival analysis in patients with advance lung adenocarcinoma a) Kaplan-Meier survival curves comparing carriers of germline PV in BRCA2 (n=22) and non-carriers(n=1854); b) Multivariate Cox proportional hazard regression analyses
See this image and copyright information in PMC

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