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Lung Cancer Study Presented at ASHG Finds Pathogenic Germline Variants in 8.5 Percent of Patients

SAN DIEGO (GenomeWeb) – About 8.5 percent of lung cancer patients carry a clinically actionable germline variant in a cancer predisposition gene, according to a new study by researchers at Memorial Sloan Kettering Cancer Center presented Wednesday at the American Society of Human Genetics annual meeting.

The majority of lung cancer cases are thought to be related to environmental factors, in particular smoking, but about 18 percent of the disease is estimated to be heritable. Rare germline variants have been identified in family studies of lung cancer, for example, and genome-wide associations studies have identified loci related to lung cancer, but most genetic risk factors for the disease remain unknown, according to Semanti Mukherjee of MSKCC's Department of Medicine.

To determine the prevalence of pathogenic germline variants in cancer susceptibility genes, she and her colleagues analyzed data from MSK-IMPACT, the center's targeted sequencing test that looks for mutations in 468 genes in a patient's tumor and matched normal samples. MSKCC started returning germline information from the test to patients in 2015 and researchers reported first results from that program earlier this year

For their analysis, Mukherjee and her colleagues studied lung cancer patients tested with MSK-IMPACT between 2014 and 2016. Specifically, they looked at an unselected cohort of about 2,700 patients and at an enriched cohort of 73 patients who either had early-onset cancer, multiple primary tumors, or a family history of cancer.

Of the unselected lung cancer patients, 228, or about 8.5 percent, were found to carry pathogenic or likely pathogenic germline variants in one of 27 cancer predisposition genes. That number was about the same in different subtypes of lung cancer, including squamous cell carcinoma, lung adenocarcinoma, and small cell lung cancer. 

In the enriched cohort, a higher fraction —17 patients, or 23 percent — carrieda pathogenic or likely pathogenic germline variant in one of 10 cancer susceptibility genes.

About 3.5 percent of patients in the unselected cohort had a pathogenic or likely pathogenic germline variant in one of 15 cancer predisposition genes of high or moderate penetrance, including CHEK2, BRCA2, BRCA1, FH, ATM, and TP53. A further 4 percent had such variants in one of 13 genes that have low or uncertain penetrance or recessive inheritance.

Also, because the cohort included many patients with Ashkenazi Jewish ancestry, the researchers unearthed population founder mutations in genes like CHEK2, APC, MUTYH, and BRCA1, which they excluded from further analysis. 

About 15 percent of patients with germline variants, especially in high or moderate penetrance genes, had a loss of heterozygosity of the wild type allele in their tumor. The researchers also looked for mutational signatures in the tumors and whether they were correlated with any germline mutations. In about 4 percent of patients, they found a signature that appears to be related to mutations in BRCA1 or 2.

Going forward, germline mutation results may guide the treatment of lung cancer patients, Mukherjee said, as well as inform their families about inherited cancer risk.