Rare inherited MUC16 variants may underlie multiple lung cancers in one family

A single family has given researchers an unusual window into the genetics of lung cancer. In a case report published in Discover Oncology, clinicians describe four siblings who each developed multiple primary lung adenocarcinomas, while a fifth sibling developed bladder cancer. Genetic testing of the family revealed that the four siblings with lung cancer, and one additional family member who went on to develop lung cancer two years later, all carried three rare germline MUC16 mutations — variants present in inherited DNA — that were absent in the sibling with bladder cancer. The authors suggest these variants may contribute to familial susceptibility to lung cancer, while cautioning that further functional and mechanistic studies are needed to clarify any role in tumorigenesis.

The team used a 474-gene next-generation sequencing panel on tumor tissue and whole-exome sequencing on matched blood samples to identify somatic and germline mutations, validating findings with ARMS-PCR and Sanger sequencing. EGFR mutations — p.L858R and/or exon 19 deletions including p.E746_A750del and p.L747_S752del — were detected in the tumor tissues of all four lung cancer patients. Notably, different lesions from the same patient showed distinct molecular profiles, which, together with histopathological assessments, supported the diagnosis of synchronous multiple primary lung cancers rather than metastatic spread from a single tumor.

The report is framed against a broader gap: the genetic etiology of hereditary lung cancer remains largely unexplored. Because the MUC16 variants appeared in every family member who developed lung cancer but not in the sibling with bladder cancer, the authors propose they may mark inherited susceptibility within this family. However, this is a single-family case report, and the findings are associative; the variants’ biological effect on lung cancer development has not been demonstrated, and the authors explicitly state that further functional and mechanistic studies are warranted.

As an open-access article published on 28 October 2026, the report is being shared early as peer-reviewed, accepted research that is citable and carries a permanent DOI, subject to further edits before the final version of record. For now, the study documents a striking pattern — four siblings with multiple primary lung adenocarcinomas, shared EGFR mutations in their tumors, and a shared set of rare germline MUC16 variants — offering a starting point for research into inherited lung cancer risk.

Subject of Research: Rare germline MUC16 variants in a family with multiple primary lung adenocarcinomas

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

Article References: Shao, C., Liu, Z., Pu, Y., Liu, F., Gao, C., Tang, M., & Liu, H. (2026). Rare germline MUC16 variants in a family with multiple primary lung cancer: a case report. Discover Oncology. https://doi.org/10.1007/s12672-026-06190-8

Image Credits: AI Generated

DOI: 10.1007/s12672-026-06190-8

Keywords: MUC16, germline mutations, lung adenocarcinoma, multiple primary lung cancer, EGFR mutations, next-generation sequencing, whole-exome sequencing, familial cancer, case report, Discover Oncology, Rare, germline