Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair–targeted therapies

Abstract

Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance. To assess the extent of inherited susceptibility to small cell lung cancer (SCLC), the most lethal type of lung cancer, we sequenced germline exomes of 87 patients (77 SCLC and 10 extrapulmonary small cell) and considered 607 genes, discovering 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. These findings were validated in an independent cohort of 79 patients with SCLC. Loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. Identification of variants influenced medical management and family member testing in nine (10.3%) patients. Unselected patients with SCLC were more likely to carry germline RAD51 paralog D (RAD51D), checkpoint kinase 1 (CHEK1), breast cancer 2 (BRCA2), and mutY DNA glycosylase (MUTYH) pathogenic variants than healthy controls. Germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio: 1.82, P = 0.008; and 2.60, P = 0.028), and longer recurrence-free survival after platinum-based chemotherapy (P = 0.002), independent of known prognostic factors. Treatment of a patient with relapsed SCLC and germline pathogenic mutation of BRCA1 interacting protein C-terminal helicase 1 (BRIP1), a homologous recombination–related gene, using agents synthetically lethal with homologous recombination deficiency, resulted in a notable disease response. This work demonstrates that SCLC, currently thought to result almost exclusively from tobacco exposure, may have an inherited predisposition and lays the groundwork for targeted therapies based on the genes involved.

Profiling of DNA damage and repair pathways in small cell lung cancer reveals a suppressive role in the immune landscape

“…Single-nucleotide polymorphisms (SNPs) analysis of XRCC1 gene from the blood DNA in SCLC patients shows significant association with survival [ 4 ]. Whole-exome sequencing reveals that germline-mutated SCLC subtype favors with DNA repair-targeted therapies [ 5 ].…”

Genomic Features of Chinese Small Cell Lung Cancer

“…Previous studies have similarly examined the prevalence and spectrum of germline variants in SCLC patients, but they are primarily focused on limited genes or in a small subset [25]. Our ndings provide a novel insight on the SCLC with germline alterations in the Chinese population tested by an NGS panel with 618 cancer-related genes.…”

UGT1A1 Gene Polymorphism Contributes as a Risk Factor for Lung Cancer: A Pilot Study with Patients from the Amazon

“…Pulmonary carcinogenesis is a complex process, with interactions that modulate the potential risks for the disease [ 7 , 31 ]. Many studies have described how germline variants influence susceptibility to lung cancer, including those linked to smoking [ 32 , 33 , 34 ].…”