Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours

Abstract

Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high-grade brain tumours in the context of bMMRD. We performed exome sequencing of two second-cousin patients from a large consanguineous family of Indian origin with early onset of high-grade glioblastoma and astrocytoma. We identified a germline homozygous nonsense variant, p.R802*, in the PMS2 gene. Additionally, by genome sequencing of these tumours, we found extremely high somatic mutation rates (237/Mb and 123/Mb), as well as somatic mutations in the proofreading domain of POLE polymerase (p.P436H and p.L424V), which replicates the leading DNA strand. Most interestingly, we found, in both cancers, that the vast majority of mutations were consistent with the signature of POLE exo , i.e. an abundance of C>A and C>T mutations, particularly in special contexts, on the leading strand. We showed that the fraction of mutations under positive selection among mutations in tumour suppressor genes is more than two-fold lower in ultramutated tumours than in other glioblastomas. Genetic analyses enabled the diagnosis of the two consanguineous childhood brain tumours as being due to a combination of PMS2 germline and POLE somatic variants, and confirmed them as bMMRD/POLE exo disorders. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Genetic alterations analysis in prognostic stratified groups identified TP53 and ARID1A as poor clinical performance markers in intrahepatic cholangiocarcinoma

“…Furthermore, one hyper-mutated sample was identified in the PP group, that is a sample characterized by a gross excess of point mutations relative to the same tumour type as analysed here and reported in current literature 15 – 19 . In particular, this case showed a missense mutation in POLE , a gene already linked to hyper-mutated genomic profiles in previous studies 20 , 21 . Two cases without mutations were observed in the PP group while in GP groups 8 cases showed no mutation.…”

NovelPOLEpathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures

“…Although extracolonic malignancies, such as ovarian carcinoma, have been previously described, to our knowledge, this report documents only the second case of breast carcinoma associated with a germline POLE mutation (Supporting Information ; Palles et al., ). The breast carcinoma reported here was associated with an “ultra‐hypermutated” phenotype, previously seen in tumors arising in those with constitutional MMR deficiency syndrome (Andrianova et al., ; Campbell et al., ; Shlien et al., ). Here, we report the reverse phenomenon: a germline POLE variant resulting in somatic MMR deficiency and an “ultra‐hypermutated” phenotype.…”

Pediatric High Grade Gliomas in the Context of Cancer Predisposition Syndromes

“…High tumor mutational burden, which is rare in childhood cancers, has been described to be extremely specific to CMMRD [ 5 , 45 , 99 ]. This vast numbers of mutations form a “signature” that is deeply engraved on the genome.…”