• 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • Specific POLE and POLD mutations have been shown to lead


    Specific POLE and POLD1 mutations have been shown to lead to ultramutation [29]. Here we observed that specific POLE EDMs might have a distinct impact on the mutational processes, given that the mu-tational signature 10 was more abundant in ECs harboring M444K or P286R EDMs than in those harboring V411L or other EDMs. This is con-sistent with recent observations that the V411L Sevoflurane reduces
    Fig. 5. Mutational signatures of primary endometrial cancers and matched metastases. Mutational signatures of primary and metastatic endometrial cancers from 26 patients from Gibson et al. [6], sorted according to molecular subtype, color-coded according to the legend. Information on histology and molecular subtype was obtained from Gibson et al. [6] and is displayed below each case along with the number of non-synonymous somatic mutations and MSIsensor scores. HRD, homologous recombination DNA repair deficiency; MSI, microsatellite instability. †P286R POLE somatic mutation; ¥V411L POLE somatic mutation.
    exonuclease activity without completely abolishing it, whereas the P286R mutation essentially inactivates proofreading [29]. Mutational signature analysis also identified a copy-number low (endometrioid) EC with a POLE L424V EDM mutation that was not classified as of POLE sub-type by TCGA, and a uterine carcinosarcoma with a POLE P286R hotspot mutation. On the other hand, we identified two MSI (hypermutated) and one copy-number high (serous-like) EC with POLE EDM mutations
    not affecting hotspot residues lacking POLE mutational signatures. In the process of translating the molecular classification into the clinical setting [34], POLE gene sequencing is required. With increasing evidence that POLE mutations are an early event in endometrial and colorectal cancers [28,30] and that ECs harboring POLE hotspot EDMs may be sensitive to nucleoside analogs [35] or immune checkpoint inhibitors [28,36], pro-spective clinical trials focusing on the treatment of advanced POLE ECs
    Fig. 6. Mutational signatures of shared and private mutations identified in primary endometrial cancers and matched metastases. Cancer cell fractions of non-synonymous somatic mutations identified in primary endometrial cancers and metastases using ABSOLUTE [26], color-coded according to the legend. The number of non-synonymous somatic mutations identified in a given lesion is shown in parentheses on the right. Pie charts represent the mutational signatures identified in mutations shared between primary tumors and metastases (root, R) in mutations private to the primary lesion (P) and in mutations private to the metastases (M), color-coded according to the legend. The length of the branches is proportional to the number of somatic mutations that are shared/unique to a given lesion, and the number of mutations is shown alongside the branches. The percentage of small insertions and deletions (indels, I) Sevoflurane are included within parentheses next the R, P or M labels. Selected pathogenic somatic mutations are shown along their corresponding branches. For EC22, the LST scores are shown below the pie charts. EC, endometrial cancer; LST, large-scale state transition; M, metastasis; P, primary tumor; R, root. Additional plots are shown in Supplementary Fig. S5.
    are warranted. In this setting, mutational signature analysis may help to determine whether the POLE mutation not only shaped the primary tumor genome but also continues to act as the tumor driver itself, as we observed that metastases from primary POLE-mutant ECs were poten-tially driven by DNA MMR-related mutational processes.
    Defining the mutational signatures of ECs may assist in refining the classification and therapy of EC patients. With the approval of the im-mune checkpoint inhibitor pembrolizumab for advanced MSI-high/ DNA MMR-deficient cancers [37], accurate identification of MSI-driven tumors is paramount. MSI immunohistochemistry in EC has a sensitivity of 86–100% and specificity of 48–81% [38]. Using a combination of MSIsensor and MLH1 promoter hypermethylation analysis, we identi-fied all ECs classified by TCGA within the MSI (hypermutated) molecu-lar subtype. In ten of the MSI (hypermutated) tumors, however, MSI-related mutational processes accounted only for a minority of the so-matic mutations detected (Supplementary Fig. S2). Further studies are warranted to assess whether MSI-high ECs with a dominant aging mu-tational signature are less sensitive to immune checkpoint inhibitors than those with a dominant MSI mutational signature.
    HGSOCs and basal-like and/or triple-negative breast cancers often show defects in HRD and due to genetic alterations affecting this path-way, including germline and somatic BRCA1 and BRCA2 mutations, and are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors [39]. Based on the similarity in copy num-ber alterations between HGSOCs, basal-like breast cancers and copy-number high (serous-like) ECs, it has been suggested that copy-number high (serous-like) ECs may also be candidates for therapies cur-rently employed for the management of HGSOCs and basal-like breast cancers [3]. We noted, however, that despite similar levels of gene copy number alterations, the underlying DNA repair defects that shaped the genomes of the majority of copy-number high (serous-like) ECs are likely distinct from those of HGSOCs and basal-like breast cancers, given their lower levels of mutational signature 3, LST scores, average indel length and number of cases harboring bi-allelic HR-related gene alter-ations. This is further supported by the relative reduced response rates to platinum agents of uterine serous carcinomas as compared to HGSOCs [40]. Importantly, however, we did identify three endometrioid ECs with a dominant signature 3, high LSTs and bi-allelic BRCA1 alter-ations, features consistent with HRD and potential benefit from thera-pies targeting this type of DNA repair defects.