NEW YORK – Researchers at the National Cancer Institute, Georgetown University, and Walter Reed National Military Medical Center have determined that small cell lung cancer (SCLC), a disease which is currently thought to result almost entirely from exposure to tobacco, may have an inherited predisposition. The findings could result in the development of therapies that target the mutated genes.
In a paper published on Wednesday in Science Translational Medicine, the researchers described sequencing the germline exomes of 77 SCLC patients and 10 extrapulmonary small cell cancer (EPSCC) patients in order to assess the extent of inherited susceptibility to SCLC. Looking at 607 genes, they discovered 42 deleterious variants in 35 cancer-predisposition genes among 43.7 percent of patients. These findings were then validated in an independent cohort of 79 SCLC patients.
The investigators observed loss of heterozygosity in three of 14 (21.4 percent) tumors, and the identification of the variants influenced medical management and testing of family members in nine (10.3 percent) patients. Further, they said, unselected patients with SCLC were more likely to carry germline RAD51D, CHEK1, BRCA2, and MUTYH pathogenic variants than healthy controls, and germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer, as well as longer recurrence-free survival after platinum-based chemotherapy.
Senior author and NCI researcher Anish Thomas said the study had two overarching implications — one related to treatment and the other to how SCLC etiology was viewed historically. "For decades now, patients with SCLC are treated with a one-size-fits-all approach, with the same uniform treatments for all patients at diagnosis and relapse, with predictably disappointing results," he wrote in an email. "The germline genotype could provide personalized treatment options for a small but important fraction of SCLC patients."
Further, the data suggested that the view of this disease as being entirely tobacco-related will have to be rethought, as the germline genotype seems to play an important role in the formation of SCLC tumors. "Germline testing of family members of SCLC patients who harbor a cancer-predisposing germline mutation could potentially save thousands of lives through screening and prophylactic measures aimed at the cancers associated with those inherited mutations," Thomas said.
To explore the genetic basis of SCLC and EPSCC and to identify candidate susceptibility genes, the researchers sequenced the exomes of 87 unselected patients and compared the frequency of pathogenic germline variants with 53,105 cancer-free non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) cohort. Most of the patients were current or former smokers, but eight were never-smokers, three of whom had non-lung primary sites. When the researchers conducted in-depth manual analyses of variants in 607 genes, they identified 1,131 non-silent variants, of which six were deemed to be pathogenic, 45 likely pathogenic, 880 of uncertain significance, and 200 benign or likely benign. After excluding variants in non-cancer genes, a total of 42 pathogenic or likely pathogenic variants were identified in 35 genes. Most of the commonly mutated genes were related to DNA repair, and the remaining genes were involved in growth factor receptor, cell cycle, Wnt, transporter, DNA methylation, and other pathways, the researchers said.
In the entire cohort, a total of 38 patients (43.7 percent) carried pathogenic or likely pathogenic germline variants in 35 cancer predisposition genes. Three patients had more than one pathogenic germline variant. On the basis of a secondary review by a cancer geneticist, the germline genotype of nine patients influenced their medical management and testing of at-risk family members. Further, 11.5 percent of patients in the cohort had deleterious variants in genes recommended by ACMG for secondary findings, 10.3 percent of patients had deleterious variants in 24 ACMG-defined cancer genes, and 19.5 percent of patients had pathogenic variants in a panel of 77 cancer predisposition genes.
Specifically, the researchers found, inherited loss-of-function mutations in RAD51D, CHEK1, and BRCA2, which are DNA repair genes, were more frequent in the SCLC patients than in controls.
"Germline genotype was associated with favorable outcomes to DNA-damaging chemotherapies. These findings demonstrate that SCLC carcinogenesis is not only driven by tobacco exposure but may also be influenced by the germline genetic background," the authors wrote. "Our results define a subgroup of patients with SCLC in whom the germline genotype may inform prognosis and the choice of targeted therapies."