Alteration of DNA mismatch repair capacity underlying the co-occurrence of non-small-cell lung cancer and nonmedullary thyroid cancer

Shiro Fujita,Katsuhiro Masago

doi:10.1038/s41598-021-83177-1

Abstract

Both non-small-cell lung cancer cases in never-smokers and nonmedullary thyroid cancer cases have been increasing in developed countries. Some studies have shown an excess of co-occurrence of non-small-cell lung cancer and nonmedullary thyroid cancer. We aimed to clarify the underlying genetic factors that contribute to the occurrence of these two malignancies. We performed germline exome sequencing in a cohort of 9 patients with the two malignancies. In terms of candidate genes, we performed target resequencing, immunohistochemistry, and microsatellite instability testing on another cohort. Two rare missense heterozygous variants in MSH6 were identified and verified by Sanger sequencing. One available tumour specimen showed heterogeneous MSH6 status in immunohistochemistry. Further exploration with different cohorts (a total of 8 patients with the two malignancies) demonstrated that 2 out of 8 patients had a germline missense or promotor variant of MLH1 and four out of 10 tumour specimens revealed heterogeneous immunohistochemistry staining in any of the four mismatch repair proteins: MLH1, PMS2, MSH2 and MSH6. Although our cohort showed a different disease profile than Lynch syndrome, this study suggests causal roles of impaired DNA mismatch repair capacity in non-small-cell lung cancer and nonmedullary thyroid cancer.

Highlights

Both non-small-cell lung cancer cases in never-smokers and nonmedullary thyroid cancer cases have been increasing in developed countries
Abbreviations 95% CI 95% Confidence interval ALK Anaplastic lymphoma kinase DRC DNA repair capacity EGFR Epidermal growth factor receptor formalin-fixed paraffin-embedded (FFPE) Formalin-fixed paraffin-embedded gnomAD Genome aggregation database IHC Immunohistochemistry mismatch repair (MMR) Mismatch repair MSI Microsatellite instability next-generation sequencing (NGS) Next-generation sequencing nonmedullary thyroid cancers (NMTC) Nonmedullary thyroid cancer NSCLC Non-small-cell lung cancer
Of 9 sporadic patients with NSCLC and NMTC, two patients harboured MSH6 missense mutations, none of which were present in the control reference gnomAD database at an allele frequency over 0.5%

Summary

Introduction

Both non-small-cell lung cancer cases in never-smokers and nonmedullary thyroid cancer cases have been increasing in developed countries. Abbreviations 95% CI 95% Confidence interval ALK Anaplastic lymphoma kinase DRC DNA repair capacity EGFR Epidermal growth factor receptor FFPE Formalin-fixed paraffin-embedded gnomAD Genome aggregation database IHC Immunohistochemistry MMR Mismatch repair MSI Microsatellite instability NGS Next-generation sequencing NMTC Nonmedullary thyroid cancer NSCLC Non-small-cell lung cancer. In addition to the aforementioned predominant adenocarcinoma histology, lung adenocarcinoma in patients without a history of smoking has a higher frequency of positive cases of particular driver gene alterations (e.g., EGFR gene mutation and ALK gene rearrangement) than lung adenocarcinoma in ever-smokers These biologically distinct characteristics cause clinicians to take a different approach in treating these cancers, especially in cases of advanced-stage disease, where systemic chemotherapy (including molecular targeted therapy and immune checkpoint blockade therapy) is the mainstay t reatment[7,8]. Many of these candidate genes are still under investigation, and only a few germline mutations have been shown to confer an inherent predisposition to lung cancer

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