Constitutional POLE variants causing a phenotype reminiscent of constitutional mismatch repair deficiency

Abstract

Heterozygous POLE or POLD1 germline pathogenic variants (PVs) cause polymerase proofreading associated polyposis (PPAP), a constitutional polymerase proofreading deficiency that typically presents with colorectal adenomas and carcinomas in adulthood. Constitutional mismatch‐repair deficiency (CMMRD), caused by germline bi‐allelic PVs affecting one of four MMR genes, results in a high propensity for the hematological, brain, intestinal tract, and other malignancies in childhood. Nonmalignant clinical features, such as skin pigmentation alterations, are found in nearly all CMMRD patients and are important diagnostic markers. Here, we excluded CMMRD in three cancer patients with highly suspect clinical phenotypes but identified in each a constitutional heterozygous POLE PV. These, and two additional POLE PVs identified in published CMMRD‐like patients, have not previously been reported as germline PVs despite all being well‐known somatic mutations in hyper‐mutated tumors. Together, these five cases show that specific POLE PVs may have a stronger “mutator” effect than known PPAP‐associated POLE PVs and may cause a CMMRD‐like phenotype distinct from PPAP. The common underlying mechanism, that is, a constitutional replication error repair defect, and a similar tumor spectrum provide a good rationale for monitoring these patients with a severe constitutional polymerase proofreading deficiency according to protocols proposed for CMMRD.

Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision

“…Additionally, consideration may be given to initiating screening 5 years earlier in patients with a highly aggressive familial phenotype. This is particularly relevant for heterozygous carriers of specific POLE or POLD1 variants associated with severe and early-onset phenotypes that present with a congenital mismatch repair deficiency (CMMRD)-like phenotype in childhood or adolescence 290–292 . In addition to the GI phenotypes, most of the rare adenomatous polyposis syndromes are associated with an increased risk of extra-GI tumours and other phenotypic manifestations ( Table 10 ).…”

Teenage-Onset Colorectal Cancers in a Digenic Cancer Predisposition Syndrome Provide Clues for the Interaction between Mismatch Repair and Polymerase δ Proofreading Deficiency in Tumorigenesis

“…Childhood medulloblastoma, found in the patient reported by Michaeli et al [ 55 ] at age 4.5 years, is not commonly associated with LS or PPAP but is found in approximately 5% of CMMRD patients [ 14 ]. It has also been observed twice in patients with a CMMRD-like phenotype caused by specific, highly penetrant germline POLE PVs that appear to confer a stronger “mutator” effect than known PPAP-associated POLE PVs [ 16 ]. Thus, it is possible that childhood medulloblastoma is specifically associated with the germline POLE p.(E277G) variant in the digenic CPS case of Michaeli et al [ 55 ], who also presented with CMMRD-like skin CALMs (as did all of his family members who carried this POLE variant) and had an MSS tumor suggesting a strong mutational effect of the POLE variant E277G [ 58 ].…”

“…Furthermore, we previously identified de novo germline POLE PVs in three CRC patients aged 13, 14, and 20 years who had a CMMRD-like phenotype [ 16 ]. As these three POLE PVs were so far found only as somatic mutations in ultra-mutated (>50 Mut/Mb) tumors but not as germline variants in PPAP patients, we speculated that they have a stronger “mutator” effect than known PPAP-causing PVs and, therefore, cause a more severe phenotype with CRC and/or brain tumors in childhood and adolescence as well as CMMRD-like non-malignant features [ 16 , 17 ]. Interestingly, somatic POLE PVs are also enriched in AYA-CRC (11% in AYA-CRCs vs. 3% in CRCs of patients aged ≥60 years) [ 4 , 18 ].…”

A Previously Unrecognized Molecular Landscape of Lynch Syndrome in the Mexican Population

“…Finally, related to hereditary colorectal cancer, 11 variants in POLE and 6 variants in POLD1 were found. Pathogenic variants in POLE and POLD1 cause PPAP syndrome (polymerase proofreading-associated polyposis), where there is an increased risk of developing colorectal cancer [ 40 ]. In the cohort, all variants identified were VUS in colorectal cancer patients.…”