Rare germline MUC16 variants in a family with multiple primary lung cancer: a case report

The genetic etiology of hereditary lung cancer remains largely unexplored. We report a family involving four siblings with multiple primary lung adenocarcinomas and one with bladder cancer. A 474-gene next-generation sequencing (NGS) panel and whole-exome sequencing (WES) were applied to identify somatic and germline mutations from tumor tissues and matched blood samples, respectively, followed by validation using ARMS-PCR and Sanger sequencing. EGFR mutations (p.L858R and/or exon 19 deletions: p.E746_A750del, p.L747_S752del) were detected in the tumor tissues of all four lung cancer patients except for the one with bladder cancer. Different lesions from the same lung cancer patients exhibited distinct molecular profiles. Together with histopathological assessments, these findings supported the diagnosis of synchronous multiple primary lung cancers. Notably, three rare MUC16 germline mutations, rs754856910, rs754254000, and rs746152510, were detected in the four lung cancer patients and in an individual from the same family who developed lung cancer two years later, but were absent in the bladder cancer patient. These findings suggest that MUC16 germline mutations may contribute to familial susceptibility to lung cancer in this family. Further functional and mechanistic studies are warranted to elucidate the role of MUC16 germline mutations in lung tumorigenesis.