POLE mutations as an alternative pathway for microsatellite instability in endometrial cancer: Implications for Lynch syndrome testing

Abstract

Further elucidation of the genomics of endometrial cancer has the capability and promise of much needed understanding of causative factors of this disease and its hereditary predisposition, development of more effective therapeutics, and improved predictive indicators for use of chemotherapy and radiation therapy. Significant strides toward these goals have been accomplished by The Cancer Genome Atlas (TCGA) project, which has genomically characterized and distilled endometrial cancer into 4 major groups based on microsatellite instability (MSI), somatic copy number alterations (SCNAs), and somatic nucleotide substitutions. 1 These groups include: 1) an ultramutated group with a unique nucleotide change spectrum of increased cysteine-toalanine (C!A) transversion frequency; 2) a hypermutated group of cancers with MSI, most of which had mutL homolog 1 (MLH1) promoter methylation (MSI group); 3) a group of cancers with microsatellite stability (MSS) that had a relatively lower mutation frequency and low SCNAs; and 4) a serous-like group comprised of cancers with serous or mixed histology and a few high-grade endometrioid cancers, all of which harbored extensive SCNAs and a low mutation rate. 1 The ultramutated group included 17 tumors (7% of all tumors in the TCGA data set), all of which harbored mutations in the exonuclease domain of polymerase e (POLE), and was associated with improved progression-free survival (PFS) compared with all other groups, and the largest difference was observed when this ultramutated group was compared with the serous-like group.POLE and polymerase d (POLD1) belong to the B family of polymerases and are responsible for synthesizing the leading and lagging strands in eukaryotic DNA replication. 2 POLE and POLD1 form the major catalytic and proofreading units of Pole and Pold enzyme complexes, which ensure the high fidelity of DNA replication. Both POLE and POLD1 exhibit the greatest homology over their proofreading exonuclease domain (residues 268-471 and 304-517, respectively), which exhibit a high level of evolutionary conservation. It is estimated that their proofreading 3 0 to 5 0 exonuclease activity, which locates and replaces erroneous bases in the daughter strand, helps protect against genomic instability by improving the fidelity of DNA replication by at least 10-fold. 3 Several cancer genome sequencing efforts have consistently demonstrated that a small fraction of colorectal and endometrial cancers contain somatic mutations within the exonuclease domains of POLE (3% and 7% in the TCGA colorectal and uterine projects, respectively). 1,4 Contrary to POLE, very few somatic POLD1 exonuclease domain mutations (EDMs) have been detected in human cancers, whereas both germline POLD1 and POLE mutations have been reported in association with a high risk of multiple colorectal adenomas and carcinomas, whereas germline POLD1 mutations also predispose to endometrial cancers. 5 Somatic POLE EDMs in endometrial and colorectal cancers have demonstrated significant overlap; and codons 286 (a c...

Polymerase ε (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro

“…Although a few cases of POLE MSI-high EC have recently been reported, the majority of previous studies have shown that POLE-mutated EC are microsatellite-stable (MSS) [15, 16]. To evaluate MSI status in POLE-mutated tumor cell lines and whether microsatellite instability may change after prolonged in vitro cultures we tested the tumor tissue blocks and the matched cell blocks of 2 POLE patients for MSI.…”

Regression of Chemotherapy-Resistant Polymerase ϵ (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab

“…POLE-ultra-mutated tumors account for 7 to 12 % of all endometrial carcinomas (1, 2, 5, 6) and occur secondary to mutations in the exonuclease domain of POLE, a nuclear DNA polymerase endowed with intrinsic proofreading activity (5). Most of POLE-ultra-mutated cancers (including the POLE tumor of patient #1 described above) are MSI stable and cannot be recognized using clinically-approved IHC and PCR-based MSI assays (1, 5, 6). In contrast, hyper-mutated endometrial tumors may occur secondary to different genetic events such as germline mutations in one of the MMR genes (as observed in patients with Lynch syndrome, including patient # 2 above) or because of epigenetic silencing of the promoters of both alleles of the MLH1 gene (1).…”

“…In contrast, hyper-mutated endometrial tumors may occur secondary to different genetic events such as germline mutations in one of the MMR genes (as observed in patients with Lynch syndrome, including patient # 2 above) or because of epigenetic silencing of the promoters of both alleles of the MLH1 gene (1). Moreover, another group of tumors with MSI phenotype (also referred as “Lynch like” tumors) exist that exhibit loss of expression of 1 or more of the MMR genes secondary to somatic mutations (1, 6). Recent reports analyzing the genetic landscape of endometrial cancers by WES in 232 treatment-naïve endometrial cancer patients (ie, TCGA)(1) and 243 endometrial cancer patients with recurrent disease enrolled in GOG 86P (7) demonstrated that the overall frequency of ultra-mutated and hyper-mutated tumors may range from 35% (ie, 7% POLE, 28% MSI)(1) to 26 % (ie, 2% POLE, 24% MSI)(7), respectively.…”

Important molecular genetic markers of colorectal cancer

“…Although there is only a weak correlation between the presence of mutations in the exonuclease domain of Pol ε and the decrease of overall survival in MSS colorectal tumors [ 123 ], it was shown that POLE germinal mutations may be responsible for predisposition to colorectal and other cancers, including Lynch syndrome [ 122 , 124 - 126 ]. In endometrial tumors, POLE mutations can play role in the development of microsatellite instability [ 127 ].…”