12q24.33

CRCS12,FILS,IMAGEI,POLE1

Different human sporadic cancers

Somatic pathogenic mutations in the proofreading domain of POLE have been found in 8% of endometrial tumours and at lower frequencies in other tumour types such as colorectal, glioblastoma, ovary, prostate, breast or gastric cancer. These mutations seem to confer similar phenotypes regardless of the tumour tissue type. These are missense, heterozygous mutations where no second hit by either mutation or LOH seem to be required, and they are very early events, possibly initiating. Some mutations are hotspots such as P286R, S297F, V411L or S459F but other rarer mutations have also been identified (eg P286H/L, S297Y, F367S, L424V/I, P436R, M444K, A456P). These mutations affect the proofreading of the protein resulting in ultramutation with an overrepresentation of C>A. More specifically, POLE tumours have mutational signature 10 as reported by Alexandrov et al, with extremely prominent TCG>TTG and TCT>TAT substitutions and transcriptional strand bias. As a result, there is an overrepresentation of some specific missense mutations and nonsense mutations. In addition, it may explain why some cancer driver genes in POLE tumours tend to show mutations otherwise relatively uncommon such as R213X in TP53 or R88Q in PIK3CA. POLE tumours are hardly ever concomitant with microsatellite instability, although a few tumours with both phenotypes have been described, and do not seem to show chromosomal instability as their karyotype is nearly diploid.

Patients with somatic POLE driver mutations are younger on average, although they have a broad range of ages. For colorectal cancer, most mutations are right-sided so they are relatively rare in rectal cancer.

POLE tumours in endometrial cancer, colorectal cancer and glioblastoma show excellent prognosis in early disease. Similar patterns are expected in any other tumour type although it is not formally proven due to the low frequency of these mutations. Such good prognosis is because of very high immunogenicity with upregulation of immune checkpoint and other immunosuppressive genes. Accordingly, POLE proofreading pathogenic mutation is also a promising candidate biomarker for checkpoint blockade immunotherapy. They may also be sensitive to treatment with nucleoside analogs as they increase the mutation burden to a level where tumour cells are not viable.

Proofreading-associated polyposis (PPAP)

Autosomal dominant disease with high risk for endometrial and/or colorectal adenoma or carcinoma due to germline mutations in POLE or POLD1 genes.

Probably good prognosis in early disease as found with POLE somatic mutations, although not formally proven. Similarly, these patients are likely to respond to checkpoint blockade immunotherapy.