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Hum Mutat. 2019 Jan;40(1):36-41. doi: 10.1002/humu.23676. Epub 2018 Nov 20.

Novel POLE pathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures.

Author information

1
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
2
Department of Medical Genetics, The Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada.
3
Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Barcelona, Spain.
4
McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
5
Biomedical Sciences Department, School of Medicine, University de Barcelona, IDIBAPS, Barcelona, Spain.
6
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Barcelona, Spain.
7
Genetic Counselling Unit, Hospital Universitari de Vic, Barcelona, Spain.
8
Hereditary Cancer Program, Catalan Institute of Oncology, IDIBGI, Girona, Spain.
9
Department of Histopathology, King Edward Memorial Hospital, and School for Women's and Infants' Health, University of Western Australia, Perth, Australia.
10
Department of Pathology, Hospital de Bellvitge, CIBERONC, Barcelona, Spain.
11
Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.
12
Department of Medical Genetics and Cancer Research Program, Research Institute McGill University Health Centre, Montreal, Quebec, Canada.
13
Icahn School of Medicine at Mount Sinai, Department of Oncological Sciences, Mount Sinai Hospital, New York City, New York.
14
Medical Sciences Department, School of Medicine, University of Girona, Girona, Spain.
15
Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada.

Abstract

We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors, including CRC and carcinomas of the ovary and breast. Whole-exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c.833C>A; p.Thr278Lys) associated with a highly penetrant, autosomal-dominant inheritance pattern. Functional studies in yeast and demonstration of a high mutational burden in the available tumors confirmed the pathogenicity of the novel variant. Prominent POLE-deficient somatic mutational signatures were seen in the CRCs, but in contrast, a mutational signature typical of concomitant tumoral loss of POLE and mismatch-repair function (POLE-exo* /MSI) was noted in the breast cancer. The breast cancer also showed distinctive pathological characteristics that reflect the presence of both the germline POLE variant and the secondary somatic MMR alterations.

KEYWORDS:

POLE; PPAP; colorectal cancer; genetic diagnosis; hereditary cancer; mutational signatures

PMID:
30362666
DOI:
10.1002/humu.23676

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