Comprehensive genomic profiling of synchronous invasive adenocarcinoma and squamous cell carcinoma within the same lobe: a case report.

Synchronous multiple primary lung cancers are rare. The field cancerization model posits that carcinogen exposure leads to molecular damage and epigenetic reprogramming in the bronchial epithelium, predisposing individuals to multiple tumors. However, genetic factors may explain why only some individuals develop synchronous primaries. Whole genome sequencing (WGS) offers comprehensive insights into somatic mutations, structural variants, and DNA repair defects, surpassing the limitations of histology or exome sequencing. An 80-year-old male underwent left upper lobectomy. The initial biopsy suggested adenocarcinoma, but the final specimen revealed two distinct invasive carcinomas: a 2.1 cm × 1.9 cm acinar- and papillary-predominant adenocarcinoma and a 1.1 cm × 0.7 cm non-keratinizing squamous cell carcinoma. WGS identified 564 variants across both tumors, with only six shared (Jaccard index 0.022). Tumor mutational burden was moderate (6.04 mutations/Mb in adenocarcinoma; 5.24 in squamous carcinoma). Clonal relatedness metrics, including variant allele frequency and cancer cell fraction correlations, were weak, supporting independent origins. Genomic analysis revealed a truncating PMS2 alteration in the adenocarcinoma and a missense ERCC2 variant of uncertain significance in the squamous carcinoma, implicating functional compromise of mismatch repair (PMS2) and nucleotide excision repair (ERCC2) pathways, both pivotal in tobacco-related mutagenic resistance. Oncogenic pathway analysis showed distinct alterations: adenocarcinoma was enriched in MET pathway alterations, while the squamous carcinoma exhibited alterations in alternative pathways. This case demonstrates that synchronous lung cancers may result from the combined effects of carcinogen-induced field cancerization and DNA repair deficiencies. The identification of PMS2 and ERCC2 alterations provides mechanistic evidence of genetic vulnerability, highlighting the importance of counseling, surveillance, and potential DNA repair-targeted strategies.