Abstract
Background: Paired tumor-normal targeted next-generation sequencing (NGS) is primarily used to identify actionable somatic mutations, but can also detect germline variants including pathogenic germline mutations in DNA mismatch repair (MMR) genes that underlie Lynch syndrome. In the present study we examined paired NGS data from lung cancer patients to identify germline mutations in MMR genes. As lung cancer is not one of the recognized Lynch syndrome-associated neoplasms, we also investigated whether these lung cancer cases are due to Lynch syndrome or are instead sporadic cancers occurring in Lynch syndrome patients.Methods: A retrospective study of 1,179 lung cancer patients with available paired NGS data was performed to identify germline mutations in the MMR genes MLH1, MSH2, MSH6, and PMS2, and evaluate tumor mutation burden (TMB). Microsatellite instability (MSI) testing was done on select cases with MMR gene mutations by either NGS or PCR/capillary electrophoresis approach. Immunohistochemistry (IHC) for MMR proteins was performed in select patients.Results: Pathogenic or likely-pathogenic germline mutations in PMS2, MSH2, or MSH6 were detected in 0.5% (6/1,179) of lung cancer patients; three of the patients had a family history of colon or gastric cancer. The median age at diagnosis of these cases was 68.5 years old. None of these six patients exhibited MSI or loss of MMR protein expression. Among them, no second hit somatic mutations in MMR genes (including single-nucleotide variants, small insertions or deletions and copy number alterations) were detected, and the median TMB was 4.5 muts/MB. Subsequent genetic testing of family members identified new Lynch syndrome cases in two first-degree relatives.Conclusion: These data imply that lung cancers in Lynch syndrome patients are unrelated to the underlying Lynch syndrome diagnosis and occur spontaneously. Nonetheless, paired tumor-normal NGS can identify germline mutations to help reveal Lynch syndrome in cancer patients. This has important implications for cancer screening and risk reduction in these patients and their families.
Highlights
Recent studies have identified genes in which germline mutations are associated with lung cancer, even in non-smokers, including EGFR, BRCA2, TP53, and others [1, 2]
For patients harboring germline mismatch repair (MMR) gene mutations, we evaluated their somatic mutation landscape including TMB, microsatellite instability (MSI) status, MMR protein expression, and clinical and pedigree characteristics when possible based on material or information availability
To assess the prevalence of germline MMR mutations in lung cancer patients, we retrospectively reviewed the mutation profiles of 1,179 lung cancer patients who underwent genetic testing of 1,021 cancer-related genes at Geneplus-Beijing Institute (Beijing, China) between 2017 and 2018 (Supplementary Table S1, Figure 1A)
Summary
Recent studies have identified genes in which germline mutations are associated with lung cancer, even in non-smokers, including EGFR, BRCA2, TP53, and others [1, 2]. Little is known about the relationship between lung cancer risk and germline mutations that underlie common hereditary cancer syndromes, such as Lynch syndrome, which is caused by mutations in DNA mismatch repair (MMR) genes including MSH2, MSH6, MLH1, and PMS2. Given that lung cancer is not frequently reported in Lynch syndrome patients, the relationship between lung cancer risk, and germline MMR mutations requires further exploration. Paired tumor-normal targeted next-generation sequencing (NGS) is primarily used to identify actionable somatic mutations, but can detect germline variants including pathogenic germline mutations in DNA mismatch repair (MMR) genes that underlie Lynch syndrome. In the present study we examined paired NGS data from lung cancer patients to identify germline mutations in MMR genes. As lung cancer is not one of the recognized Lynch syndrome-associated neoplasms, we investigated whether these lung cancer cases are due to Lynch syndrome or are instead sporadic cancers occurring in Lynch syndrome patients
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