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

• Published in: Familial cancer 2022-04, Vol.21 (2), p.197-209
• Main Authors: Palles, Claire, Martin, Lynn, Domingo, Enric, Chegwidden, Laura, McGuire, Josh, Cuthill, Vicky, Heitzer, Ellen, Kerr, Rachel, Kerr, David, Kearsey, Stephen, Clark, Susan K., Tomlinson, Ian, Latchford, Andrew
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Brain cancer; Brain tumors; Cancer Research; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; DNA Polymerase II - genetics; Endometrial cancer; Endometrial Neoplasms - genetics; Endometrial Neoplasms - therapy; Endometrium; Epidemiology; Exonuclease; Female; Genotypes; Germ-Line Mutation; Heterozygotes; Human Genetics; Humans; Literature reviews; Malignancy; Original; Original Article; Ovarian cancer; Pathogenicity; Patients; Phenotypes; Poly-ADP-Ribose Binding Proteins - genetics; Polyposis; Propylamines; Surveillance
• ISSN: 1389-9600; 1573-7292
• DOI: 10.1007/s10689-021-00256-y

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.