For endometrial cancer, four molecular subgroups have undergone extensive studies in recent years: POLE ultramutated (POLEmut), mismatch repair-deficient (MMRd), p53 mutant (p53abn) and those EC lacking any of these alterations, referred to as NSMP (non-specific molecular profile).
After The Cancer Genome Atlas (TCGA) findings, four novel prognostic groups may direct the management of endometrial cancer (EC): POLE-mutated/ultramutated (POLEmt), microsatellite-instable/hypermutated (MSI), copy-number-low/p53-wild-type (p53wt), and copy-number-high/p53-mutated (p53mt).
The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent <i>POLE</i>-mutant cancers.<b>Experimental Design:</b> We examined the recurrence-free survival of women with <i>POLE</i>-mutant and <i>POLE-</i>wild-type endometrial cancers (EC) in the observation arm of the randomized PORTEC-1 endometrial cancer trial (<i>N</i> = 245 patients with stage I endometrial cancer for analysis).
This study provides significant evidence that analyses of proofreading POLE mutations and MSI status based on mononucleotide repeat markers are potentially useful biomarkers to identify EC patients with better prognosis.
POLE exonuclease domain mutations have recently been described in undifferentiated endometrial carcinoma but, because of the rarity of this aggressive type of endometrial cancer, their prognostic significance is unknown.
Forty-nine ECs (three tumour blocks/case) were selected with alterations in POLE (n=10), CTNNB1 (n=8), p53 (n=10), mismatch repair (n=11), L1CAM (n=10), and ECs without any of these markers (n=9).
Mean BMI was statistically different between the ECs in the CNL (35.8) versus POLE (29.8) cluster (p=0.006) and approached significance for the MSI (33.0) versus CNL (35.8) cluster (p=0.05).
POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors.
We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors.
Germline mutations in the exonuclease (proofreading) domains of 2 DNA polymerases (POLE and POLD1) have been associated with a dominantly inherited, highly penetrant syndrome of oligo adenomatous polyposis and early-age-of-diagnosis colorectal cancer and endometrial cancer.
The variants associated with susceptibility, POLEp.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition.
Here, we present the evidence for POLE and POLD1 as important contributors to the pathogenesis of CRC and EC, and highlight some of the key questions in this emerging field.