Germline Pathogenic Variants Impact Clinicopathology of Advanced Lung Cancer

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 5118 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 to non-carriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1 and MEN1) were diagnosed at younger age compared to non-carriers, and of tumor suppressors, 75% demonstrated bi-allelic inactivation in tumors. 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 to unselected patients (10.5% vs 4.1%; p-value=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.

ATM—the gene at the moment in non-small cell lung cancer

“…Ricciuti et al inferred putative germline ATM variants in 5% of 3,800 NSCLC cases based on targeted NGS of tumor DNA. This frequency was higher than what has been reported for germline ATM variants in lung tumors by previous studies (0.5–1.9%), although they were not restricted to NSCLC ( 5 , 6 , 19 , 20 ). One approach for differentiating germline from somatic variants is to utilize variant allele fraction (VAF) and copy number status since high VAF and loss-of heterozygosity may flag putative germline alleles ( 19 ).…”

“…Moreover, clinical follow-up often extends beyond the individual carrying the PV, with cascade testing done to identify family members who are also at risk. Recent reports that 4–15% of lung cancers harbor PVs not only in ATM but also in BRCA1 , BRCA2 , and CHEK2 ( 5 , 19 , 20 ) emphasize that studies to understand the clinical significance of these variants are also warranted since they could inform the clinical management of patients.…”

Characterization of Incidental Pathogenic Germline Findings Detected via ctDNA among Patients with Non-Small Cell Lung Cancer in a Predominantly Hispanic/Latinx Population

“…A significantly higher proportion of high-penetrance PGVs predisposing patients to lung cancers, including TP53 , EGFR , and BAP1 , have been detected in patients who had multiple primary tumors, family history of any cancer, or early age of diagnosis compared to noncarriers [ 29 ]. In addition, patients with a family history of lung cancer have been shown to have an increased incidence of cancer regardless of tobacco use, indicating that genetic characteristics increase the likelihood of smokers and non-smokers alike developing lung cancer [ 30 , 31 , 32 ].…”

“…One study that examined PGVs in lung adenocarcinoma found them to occur at a comparable or slightly lower rate as TCGA at 2.5–4.5%, and also found that mutations most commonly occurred in ATM (50%), followed by TP53 (28.6%), BRCA2 , EGFR , and PARK2 , all (7.1%) [ 42 ]. However, another study that compared the rate of prevalence of BRCA1 and BRCA2 PGVs in patients with lung adenocarcinoma with ATM PGVs reported a higher prevalence of BRCA1 and BRCA2 PGVs [ 29 ]. While ATM germline variant testing was not previously recommended by the European Society for Medical Oncology (ESMO) Precision Medicine Working Group as a common inclusion for clinical germline testing, it is now recommended for patients undergoing testing for actionable pathogenic variants in addition to seven ‘most actionable’ cancer-susceptibility genes ( BRCA1 , BRCA2 , PALB2 , MLH1 , MSH2 , MSH6 , and RET ) for which germline investigation is recommended—regardless of tumor type [ 43 , 44 ].…”

Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology

“… 2 However, the World Health Organization (WHO) declares many other carcinogens including indoor radon gas, environmental pollution, asbestos, occupational exposure, or radiation. 3 Recent evidence shows that beyond external carcinogens, ethnicity 4 and genetic predisposition (associated with germline pathogenic variants in well-known high/moderate-penetrance cancer predisposition genes) 5 may also play a crucial role in lung cancer risk and the molecular profile of the lung tumor.…”