The clinical features of polymerase proof-reading associated polyposis (PPAP) and recommendations for patient management

Fam Cancer. 2022 Apr;21(2):197-209. doi: 10.1007/s10689-021-00256-y.

Claire Palles ¹, Lynn Martin ², Enric Domingo ³, Laura Chegwidden ⁴, Josh McGuire ⁵, Vicky Cuthill ⁶, Ellen Heitzer ⁷, CORGI Consortium, Rachel Kerr ³, David Kerr ⁸, Stephen Kearsey ⁹, Susan K Clark ⁶ ¹⁰, Ian Tomlinson ², Andrew Latchford ⁶ ¹⁰

Affiliations

1 Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK. c.palles@bham.ac.uk.
2 Edinburgh Cancer Research Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
3 Department of Oncology, Old Road Campus Research Building, University of Oxford, Roosevelt Drive, Oxford, UK.
4 Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
5 Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
6 Polyposis Registry, St Mark's Hospital, Harrow, London, HA1 3UJ, UK.
7 Diagnostic and Research Institute of Human Genetics, University of Gratz, Graz, Austria.
8 Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
9 ZRAB, University of Oxford, 11a Mansfield Road, Oxford, OX1 3SZ, UK.
10 Department of Surgery and Cancer, Imperial College London, London, UK.

PMID: 33948826 DOI: 10.1007/s10689-021-00256-y

Abstract

Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from Cancer genetics clinics, a colorectal Cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial Cancer or any Cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal Cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial Cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian Cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of Other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype-phenotype associations, these recommendations should apply to all PPAP patients.

Keywords

Exonuclease domain mutation; POLD1; POLE; PPAP.

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