Information for Health Professionals, Polyposis

DNA polymerase proofreading associated-polyposis (PPAP): A new syndrome


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PAP family

Polymerase proofreading associated polyposis
(PPAP) is the suggested name for the condition predisposed by pathogenic mutations in the exoncuclease/proof reading domain of the POLE and POLD1 genes. This leads to a heritable susceptibility to developing multiple adenomas and/or early onset colorectal cancer.  The phenotype of PPAP is similar to that seen with MutYH associated polyposis (multiple adenomas) or Lynch syndrome (large adenomas or early onset carcinoma). Mutations in POLD1 are also associated with development of endometrial carcinoma.  Tumours tend to be microsatellite stable.

Mutations in related DNA polymerase genes POLE and POLD1 were described in families with oligopolyposis and endometrial cancer by Ian Tomlinson’s group in Oxford. An elegant approach was employed using whole-genome sequencing in 15 selected patients with more than ten adenomas before age 60 years. Several had a close relative with at least five adenomas who could also have whole-genome sequencing performed. All tested patients had CRC or a first-degree relative with CRC. All had negative APC, MYH, and MMR gene mutation test results. No variants were found to be in common among the evaluated families. In one family, however, linkage had established shared regions, in which one shared variant was found (POLE p.Leu424Val; c.1270C>G), with a predicted major derangement in protein structure and function. In a validation phase, nearly 4,000 affected cases enriched for the presence of multiple adenomas were tested for this variant and compared with nearly 7,000 controls. In this exercise, 12 additional unrelated cases were found to have the L424V variant, with none of the controls having the variant. In the affected families, inheritance of multiple-adenoma risk appeared to be autosomal dominant. Somatic mutations in tumors were generally consistent with the otherwise typical chromosome instability (CIN) pathway, as opposed to MSI or CIMP. No extracolonic manifestations were seen. A similar approach, whole-genome testing for shared variants, with further “filtering” by linkage analysis identified a variant in the POLD1 gene, p.Ser478Asn alteration, c.1433G>A). This S478N variant was identified in two of the originally evaluated families, suggesting evidence of common ancestry. The validation exercise showed one patient with polyps with the variant but no controls with the variant. Somatic mutation patterns were similar to the POLE variant. Several cases of early-onset endometrial cancer were seen. The mechanism underlying adenoma and carcinoma formation resulting from the POLE L424V variant appeared to be a decrease in the fidelity of replication-associated polymerase proofreading. This in turn appeared to lead to mutations related to base substitution.

 

The study authors recommend consideration of POLE and POLD1 testing in patients with multiple or large adenomas in whom alternatives mutation testing is uninformative and surveillance akin to that afforded patients with LS or MAP. POLE and POLD1 mutation testing is being incorporated into the new multigene CRC susceptibility panels.

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About kjmonahan

Service lead for Family History of Bowel Cancer Clinic

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