High frequency of germline mutations in DDR associated genes SLX4, MSH6, CDK4, TSC2, and BRCA2 might contribute to the occurrence of MPLC.

Abstract

e20514 Background: Multiple primary lung cancer (MPLC) is the presence of two or more distinct and separate lung tumors in a single patient. Each is considered a primary tumor rather than a metastasis from another site. This phenomenon has been the subject of several studies in recent years due to its increasing incidence and potential implications for patient management and prognosis. The underlying causes of MPLCs are not fully understood. Still, several factors have been proposed to contribute, including the genetic predisposition of carcinogens, such as those in the TP53, BRCA1, and BRCA2 genes, which are associated with an increased risk of developing MPLCs, as well as other cancers. Whether the presence of germline genetic mutations can increase an individual's susceptibility and contribute to the development of MPLCs is not clear yet. Here we reported the landscape of germline mutations of 77 MPLC patients. Methods: We retrospectively analyzed the somatic and germline mutations from 77 MPLC patients by NGS analysis. The GO and KEGG analyses were performed based on the top 30 most frequent germline mutations. Results: Among the 77 patients, 21 (27.27%) were male, and 56 (72.73%) were female. The median age was 60 (26-82) years old. The top 5 frequent germline mutated genes were SLX4 (34.92%), MSH6 (39.68%), CDK4 (26.98%), TSC2 (25.4%), and BRCA2 (25.4%). The top 5 frequent somatic mutated genes were EGFR (80.95%), CDK4 (26.98%), MCL1 (23.81%), SOCS1 (19.05%), and TP53 (19.05%). GO analysis of germline mutations revealed enrichment in ontologies such as response to radiation and UV, cell cycle regulation, a series of DNA damage repair associated ontologies, and telomere organization. KEGG analysis indicated that these germline mutations were enriched in the PI3K-Akt pathway, microRNAs in cancer, TP53 pathway, Fanconi anemia pathway, cellular senescence, and many other cancer-associated pathways. Conclusions: Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. In our analysis, the MPLC patients contained widespread germline mutations in SLX4, MSH6, CDK4, TSC2, and BRCA2, which were all associated with DNA damage repair. Besides, GO analysis and KEGG analysis also revealed enrichment in DDR-associated ontologies or pathways (e.g., TP53 pathway, Fanconi anemia pathway, cellular senescence pathways). To our knowledge, an underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. The widespread of germline mutations in DDR-associated genes, including SLX4, MSH6, CDK4, TSC2, and BRCA2, might contribute to the gene instability and promote the development of MPLC.