POLE proofreading mutations cause ultrahypermutant-phenotype in colorectal cancer (CRC) but the characters of POLE mutations are still obscure in contrast to Lynch syndrome or sporadic microsatellite instability (MSI). Herein, we examined mutation profiles of POLE in 1,039 CRC Japanese patients, and tried to clarify clinico-pathological features of hypermutant CRC patients with respect to POLE mutations, Lynch syndrome and sporadic MSI.
We analyzed POLE pathogenic hotspot (exon9, 13 and 14), BRAF codon 600 and KRAS exon 2 mutations by Sanger sequencing. MSI status was confirmed by a multiplex PCR assay. MSI positive cases were confirmed the four mismatch repair (MMR) proteins (MLH1, MSH2, PMS2, and MSH6) expression. Germline mutations were analyzed by Sanger sequencing and a TruSight One Sequencing Panel using a next generation sequencer.
Of 1,039 CRC patients, only four cases showed POLE pathogenic mutations (two P286R, one V411L and one S459F). The four POLE-mutant CRCs showed no MSI. CRC with MMR deficient (=MSI) were observed in 58 cases (5.6%). Of CRCs with MSI, Lynch syndrome was found in 17 cases and the rest of 41 cases were sporadic MSI. Therefore, we divided 1,039 CRCs into the four subsets; POLE-mutant (POLE; n = 4, 0.4%), Lynch syndrome (LS; n = 17, 1.6%), sporadic MSI (MSI; n = 41, 4.0%), and non-hypermutant CRCs (NH; n = 997, 94.0%). Mean age at diagnosis in POLE/LS/MSI/NH was 52.5/55.7/73.6/65.9 years, respectively (P< .0001). Frequency of female in POLE/LS/MSI/NH was 50/23.5/61/41% (P = 0.03). The primary tumor located at the right colon was observed in 100/35/80.5/30% of POLE/LS/MSI/NH (P< .0001). BRAF mutation was observed in 49% of MSI and 4% of NH while KRAS mutation was in 35% of LS and 32% of NH (P< .0001). Interestingly, 100/82/78% of POLE/LS/MSI tumors were diagnosed at the earlier stage, I or II, while 46% of NH (P< .0001). The recurrence free survival rate at 5-years was better in POLE (100%)/LS (86%)/MSI (94%) compared with that in NH (74%).
POLE-mutant CRC was rare, observed in the younger without family history, located at the right colon, and diagnosed at the earlier stage.
Clinical trial identification
Legal entity responsible for the study
The Ministry of Education, Culture, Sports, Science and Technology (MEXT).
All authors have declared no conflicts of interest.