Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

Abstract

Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown. Here, we have shown that pathogenic POLE mutations are detectable in non‐malignant precursors of endometrial and colorectal cancer. Using genome and exome sequencing, we found that multiple driver mutations in POLE‐mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis. In POLE‐mutant cancers, the proportion of monoclonal predicted neoantigens was similar to that in other cancers, but the absolute number was much greater. We also found that the prominent CD8+ T‐cell infiltrate present in POLE‐mutant cancers was evident in their precursor lesions. Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur. The resulting early onset of genomic instability may account for the striking immune response and excellent prognosis of these tumours, as well as their early presentation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

“…In support of this, we observed a trend of higher somatic mutation burden in OC patients with germline ANKRD11 and POLE ‐mutations. This finding is consistent with what has been observed in endometrial and colorectal tumors with somatic POLE ‐mutations . In addition, it might also raise the beneficial potential of including POLE in gene panel testing of OC patients and their family members in order to optimize the prevention strategies to decrease their risk of OC and colorectal cancer.…”

“…Our finding is consistent with recent findings that POLE mutations can contribute to susceptibility to a broad cancer spectrum including OC. 34,35 Furthermore, it has also been reported that POLEmutant endometrial and colorectal tumors had a high somatic mutation burden, elevated expression of immune checkpoint genes and increased lymphocytic infiltration, [36][37][38][39][40][41][42][43] and therefore immune checkpoint inhibitors was recommended for treating cancers with POLE-mutations. 41,44 Similar recommendation was also demonstrated in mismatch repair (MMR) deficient cancers regardless of the cancers' tissue of origin.…”

“…This finding is consistent with what has been observed in endometrial and colorectal tumors with somatic POLE-mutations. 40,42,43 In addition, it might also raise the beneficial potential of including POLE in gene panel testing of OC patients and their family members in order to optimize the prevention strategies to decrease their risk of OC and colorectal cancer. We noticed POLE variants were more prevalent in the TCGA OC cohort than in our discovery cohort (4.34% vs. 2.53% in Table 2).…”

Molecular Subtype Not Immune Response Drives Outcomes in Endometrial Carcinoma

“…Moreover, the presence of TIL is associated, albeit imperfectly, with clinical response to immunotherapies targeting the CTLA-4 and PD-1 pathways, referred to as "checkpoint blockade" (5)(6)(7). TIL responses generally show a positive association with mutation load, presumably due to an increased number of mutated antigens (neoantigens) available for T-cell recognition (8,9). In addition, DNA damage can promote TIL responses by activating mechanisms such as the cGAS/STING pathway (10), leading to an immunologically permissive tumor microenvironment.…”

Systemic treatment for metastatic colorectal cancer in the era of precision medicine

“…Exonuclease domains of DNA polymerase δ ( POLD ) and Polymerase ɛ ( POLE ) are critical components of the normal DNA replication process and provide an essential proofreading function. Mutations in POLE and POLD occur in approximately 1% of colorectal cancers and have been associated with an ulltramutated tumor status (very high tumor mutation burden) and increased tumor PD‐L1 expression and infiltration with cytotoxic lymphocytes . These tumors are associated with a decreased risk of recurrence and are underrepresented in the setting of metastatic disease in comparison to earlier stages of CRC .…”