The somatic POLE P286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy.
Early-onset colorectal cancers (EOCRCs) may have biological or genomic features distinct from late-onset CRCs (LOCRCs). Previous studies have mostly focused on the germline predisposition conditions of EOCRCs, but we hypothesized that EOCRCs may have distinct somatic aberrations that accelerate cancer development. To identify the somatic aberrations that accelerate cancer development at an early age, we conducted whole exome sequencing for 28 polyposis-unrelated, microsatellite stable (MSS) EOCRCs with no known germline predisposition conditions. Surprisingly, we found two distinct groups in the context of mutational burden: 6 hypermutated cases with 2325 to 10973 mutations and 22 nonhypermutated cases with 47 to 154 mutations. Further analysis revealed that four of the six hypermutated cases had the same POLE P286R mutation. We validated this finding in 83 MSS EOCRCs and 27 MSS LOCRCs, which revealed that 7.2% of EOCRCs (6/83) had the POLE P286R mutation, which was not found in LOCRCs. Clinicopathologically, EOCRCs with POLE mutations occurred far more frequently in the right colon than in the left colon, affecting men more frequently than women. In summary, we have identified a unique subclass of colon cancer characterized by a hypermutation associated with the POLE mutation. The acquisition of the POLE mutation leading to hypermutation can accelerate cancer development. Clinically, this subset with hypermutation may be susceptible to immune checkpoint blockade.
Division of Hematology-Oncology, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, South Korea.|Gachon Institute of Genome Medicine and Science, Gachon University Gil Hospital, Incheon, South Korea.
Sung-Min
SM
Ahn
Department of Biomedical Engineering, University of Ulsan College of Medicine, Seoul, South Korea.|Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.
Adnan Ahmad
AA
Ansari
Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.|Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Jihun
J
Kim
Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.
Deokhoon
D
Kim
Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.|Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Sung-Min
SM
Chun
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Jiyun
J
Kim
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Tae Won
TW
Kim
Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Inja
I
Park
Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Chang-Sik
CS
Yu
Asan Center for Cancer Genome Discovery, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.|Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Se Jin
SJ
Jang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004257:DNA Polymerase II / Q000235:genetics* / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005260:Female; D023281:Genomics / Q000379:methods; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D020125:Mutation, Missense; D000075223:Poly-ADP-Ribose Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA / Q000379:methods
D014408:Biomarkers, Tumor; D000075223:Poly-ADP-Ribose Binding Proteins; D004257:DNA Polymerase II; C119525:POLE protein, human
PD-1 blockade; POLE; early-onset colorectal cancer; hypermutation; immunotherapy