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

Claire Palles,Susan K Clark,The Corgi Consortium ,Stephen Kearsey,Ellen Heitzer,Lynn Martin,David Kerr,Rachel Kerr,Laura Chegwidden,Vicky Cuthill,Enric Domingo,Ian Tomlinson,Josh Mcguire,Andrew Latchford

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.

Highlights

It has historically been thought that Mendelian cancer predisposition syndromes are rarely, if ever, associated with a general predisposition to cancer
We report the clinical features of a set of families with polymerase proofreading-associated polyposis (PPAP), a Mendelian dominant condition caused by pathogenic variants in the exonuclease domains of POLE and POLD1, the genes encoding the catalytic subunits of DNA polymerases epsilon and delta
We have provided a comprehensive description of the clinicopathological features of polymerase proof-reading associated polyposis (PPAP) in those heterozygous for POLE and POLD1 exonuclease domain (ED) variants with supporting evidence of a pathogenic impact

Summary

Introduction

It has historically been thought that Mendelian cancer predisposition syndromes are rarely, if ever, associated with a general predisposition to cancer. Reports of the spectrum of cancers associated with particular high-penetrance gene defects have often been revised in the light of improved treatment, longer follow-up and identification of gene heterozygotes in extended pedigrees. Almost without exception, these studies have confirmed that the cancers originally described are the major risks, but lesser increased risks of other cancers are present. Well established examples of the latter include prostate cancer in BRCA1 and BRCA2 heterozygotes [1], gastric cancer in individuals with LiFraumeni syndrome [2] and head and neck squamous cell cancer, gynaecological squamous cell cancer, oesophageal cancer, and liver, brain, skin and renal tumours in Fanconi anaemia patients [3]

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