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

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

doi:10.1038/s41698-022-00258-8

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

NPJ Precis Oncol. 2022 Mar 8;6(1):15. doi: 10.1038/s41698-022-00258-8.

Authors

Enrico Berrino^{1

2}, Roberto Filippi^{3

4}, Clara Visintin⁵, Serena Peirone^{1

6}, Elisabetta Fenocchio¹, Giovanni Farinea¹, Franco Veglio^{2

7}, Massimo Aglietta^{1

3}, Anna Sapino^{1

2}, Matteo Cereda^{1

6}, Rosella Visintin⁵, Barbara Pasini^{8

9}, Caterina Marchiò^{10

11}

Affiliations

¹ Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy.
² Department of Medical Sciences, University of Turin, Turin, Italy.
³ Department of Oncology, University of Turin, Turin, Italy.
⁴ Medical Oncology Unit, University Hospital AOU Città della Salute e della Scienza, Turin, Italy.
⁵ Department of Experimental Oncology, European Institute of Oncology, IEO IRCCS, Milano, Italy.
⁶ Cancer Genomics and Bioinformatics Unit, IIGM-Italian Institute for Genomic Medicine, c/o IRCCS Candiolo, 10060, Turin, Italy.
⁷ Internal Medicine Unit, University Hospital AOU Città della Salute e della Scienza, Turin, Italy.
⁸ Department of Medical Sciences, University of Turin, Turin, Italy. barbara.pasini@unito.it.
⁹ Medical Genetics Unit, University Hospital AOU Città della Salute e della Scienza, Turin, Italy. barbara.pasini@unito.it.
¹⁰ Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy. caterina.marchio@unito.it.
¹¹ Department of Medical Sciences, University of Turin, Turin, Italy. caterina.marchio@unito.it.

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.

Abstract

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