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

Enrico Berrino,Giovanni Farinea,Matteo Cereda,Caterina Marchiò,Rosella Visintin,Serena Peirone,Elisabetta Fenocchio,Roberto Filippi,Massimo Aglietta,Anna Sapino,Barbara Pasini,Franco Veglio,Clara Visintin

doi:10.1038/s41698-022-00258-8

Abstract

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.

Highlights

The onset of multiple neoplasms in young patients is highly suggestive of predisposition variants in genes associated with tumorigenesis
Examples are represented by BRCA1/2 variants in hereditary breast and ovarian carcinomas, MUTYH and NTHL1 variants in multiple colorectal polyps and cancer, and mutations in the mismatch repair (MMR) genes that predispose to Lynch syndrome, with high risk for colorectal cancer (CRC) and extra-colonic neoplasms[3]
Surgical resection led to a final diagnosis of adenocarcinoma with prominent mucinous features in one of the two lesions, pT4a(m) pN1b (Fig. 1a)

Summary

Introduction

The onset of multiple neoplasms in young patients is highly suggestive of predisposition variants in genes associated with tumorigenesis. Loss-of-function of these genes (mainly MLH1, MSH2, MSH6, and PMS2) reduce the post-replicative capabilities of repairing sequence errors inserted by the most active DNA polymerases, polymerase epsilon catalytic subunit A (encoded by POLE), and polymerase delta catalytic subunit (encoded by POLD1) whose exonuclease domain proofreads and repairs mis-embedded bases[4], leading to microsatellite instability (MSI). Mutations in this domain cause an inherited multiple polyposis and cancer predisposition[5] but they can be somatically acquired. MMR deficiency and POLE/POLD1 mutations are correlated with hypermutated/MSI and with ultra-mutator phenotypes, respectively[6], and have gained interest as positive predictors of immunotherapy response[7–10]

Methods

Results

Conclusion