Collision of germline POLE and PMS2 variants in a young patient treated with immune checkpoint inhibitors

The onset of multiple and metachronous tumors in young patients induces to suspect the presence of genetic variants in genes associated with tumorigenesis. We describe here the unusual case of a 16-year-old patient who developed a synchronous bifocal colorectal adenocarcinoma with distant metastases. We provide high throughput molecular characterization with whole-exome sequencing (WES) and DNA targeted sequencing of different tumoral lesions and normal tissue samples that led to unveil a germline POLE mutation (p.Ser297Cys) coexisting with the PMS2 c.2174 + 1 G > A splicing mutation. This clinical scenario defines a POLE-LYNCH collision syndrome, which explains the ultra-mutator phenotype observed in the tumor lesions, and the presence of MMR deficiency-associated unusual signatures. The patient was successfully treated with immune checkpoint inhibitors but subsequently developed a high-grade urothelial carcinoma cured by surgery. We complement this analysis with a transcriptomic characterization of tumoral lesions with a panel targeting 770 genes related to the tumor microenvironment and immune evasion thus getting insight on cancer progression and response to immunotherapy.

Automated summary

The presence of multiple and metachronous tumors in young patients may be associated with genetic variants. This study describes the case of a 16-year-old patient with synchronous bifocal colorectal adenocarcinoma and distant metastases. Molecular characterization and transcriptomic analysis revealed a POLE-LYNCH collision syndrome, explaining the observed ultra-mutator phenotype and MMR deficiency-associated features.