3 years ago

Germline PMS2 and somatic POLEexo mutations cause hypermutability of the leading DNA strand in Biallelic Mismatch Repair Deficiency syndrome brain tumors

Sergey I Nikolaev, Pascale Ribaux, Jean-Louis Blouin, Madathan Kandi Sibin, Stylianos E Antonarakis, Ghati Kasturirangan Chetan, Vladimir B. Seplyarskiy, Rao KVL Narasinga, Doron Merkler, Maria A. Andrianova, Periklis Makrythanasis, Thomas Mckee
Biallelic Mismatch Repair Deficiency (bMMRD) in tumors is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1 and results to a characteristic mutational profile. In this study we describe the genetic basis of ultramutated high grade brain tumors 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 R802X in the PMS2 gene. Additionally, by genome sequencing of these tumors we have observed extremely high somatic mutation rates (237 and 123 mut/Mb) as well as somatic mutations in the proofreading domain of POLE polymerase (P436H and L424V), that replicates the leading DNA strand. Most interestingly, we have observed in both cancers that the vast majority of mutations were consistent with the signature of PolE exo-, i.e. the 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 tumor suppressor genes is more than 2-fold lower in ultramutated tumors compared to other glioblastomas. Genetic analyses enabled the diagnosis of the two consanguineous childhood brain tumors due to a combination of PMS2 germline and POLE somatic variants and confirmed them as a bMMRD/POLEexo- disorder.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/path.4957

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