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

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

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)197–209
JournalFamilial Cancer
Publication statusPublished - 5 May 2021

Keywords / Materials (for Non-textual outputs)

  • POLE
  • POLD1
  • PPAP
  • exonuclease domain mutation


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