Abstract
In a 14-year-old boy with polyposis and rectosigmoid carcinoma, we identified a novel POLE germline mutation, p.(Val411Leu), previously found as recurrent somatic mutation in ‘ultramutated’ sporadic cancers. This is the youngest reported cancer patient with polymerase proofreading-associated polyposis indicating that POLE mutation p.(Val411Leu) may confer a more severe phenotype than previously reported POLE and POLD1 germline mutations. The patient had multiple café-au-lait macules and a pilomatricoma mimicking the clinical phenotype of constitutional mismatch repair deficiency. We hypothesize that these skin features may be common to different types of constitutional DNA repair defects associated with polyposis and early-onset cancer.
Highlights
Faithful DNA replication of human cells is safeguarded by two mechanisms: (1) proofreading by an exonuclease activity intrinsic to the replication polymerases, and (2) DNA mismatch repair (MMR) [1]
In a 14-year-old boy with polyposis and rectosigmoid carcinoma, we identified a novel POLE germline mutation, p.(Val411Leu), previously found as recurrent somatic mutation in ‘ultramutated’ sporadic cancers
Cell-free experiments show comparable effects of the somatic hotspot POLE mutation p.(Val411Leu) and the recurrent germline mutation p.(Leu424Val) on exonuclease activity [12], the detection of p.(Val411Leu) as a constitutional mutation in this 14-year-old cancer patient suggests that this POLE mutation confers a more severe phenotype than the previously reported POLE and POLD1 germline mutations [3]
Summary
Faithful DNA replication of human cells is safeguarded by two mechanisms: (1) proofreading by an exonuclease activity intrinsic to the replication polymerases, and (2) DNA mismatch repair (MMR) [1]. Polymerase proofreading-associated polyposis (PPAP, MIM 612591 and 615083) results from heterozygous missense POLD1 and POLE exonuclease domain mutations (EDMs) inactivating the proofreading activity of the replicative polymerases, Pol d and Pol e, respectively [2]. CMMRD manifests with non-malignant features, which serve as diagnostic signposts for this recessively inherited childhood cancer syndrome [7]. CALMs and pilomatricomas, serve as diagnostic features in a 3-point scoring system, recently established by the European consortium ‘‘Care for CMMRD’’ (C4CMMRD) [7]. According to this scoring system, any pediatric/young adult cancer patient reaching a minimum of 3 scoring points is suspected of having CMMRD
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