Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinomas.
BACKGROUND
Although colorectal mucinous adenocarcinomas (MCs) are conventionally regarded as exhibiting high-grade differentiation, they can be divided by differentiation into 2 groups according to the glandular appearance: low-grade mucinous adenocarcinoma (low-MC) and high-grade mucinous adenocarcinoma (high-MC).


METHODS
Patients with colorectal cancer (CRC) who underwent surgical resection between 2000 and 2012 were enrolled in this study. Among the cases with MC, the clinicopathological and genetic differences between low-MC and high-MC were investigated with next-generation sequencing.


RESULTS
A total of 1373 patients with CRC were analyzed. Forty patients (2.9%) had MC, and 13 patients had high-MC. Patients with MC had significantly shorter disease-free survival (DFS) and overall survival (OS) periods than those with nonmucinous carcinoma. When low-MC patients and high-MC patients were compared, those with high-MC had significantly shorter DFS and OS periods than those with low-MC. Multivariate analyses revealed that high-MC was significantly associated with both shorter DFS and shorter OS, but low-MC was not. A genome analysis revealed that low-MC had a considerably larger number of mutations than high-MC, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and adenomatous polyposis coli mutations were particularly frequently found in low-MC. In contrast, SMAD family member 4 (SMAD4) mutations were frequently found in high-MC.


CONCLUSIONS
High-MC is an independent prognostic factor in CRC (but low-MC is not), and it is genetically different from other CRCs, including low-MC. Both the clinicopathological differences and the genetic differences suggest that low-MC and high-MC should be distinguished in clinical settings.
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.|Department of Surgery, Faculty of Medicine, Kinki University, Osaka, Japan.
Yasumasa
Y
Yoshioka
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.
Yosuke
Y
Togashi
Department of Pathology, Faculty of Medicine, Kinki University, Osaka, Japan.
Takaaki
T
Chikugo
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.|Department of Surgery, Faculty of Medicine, Kinki University, Osaka, Japan.
Akihiro
A
Kogita
Department of Biostatistics, Yokohama City University School of Medicine, Kanagawa, Japan.
Masataka
M
Taguri
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.
Masato
M
Terashima
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.
Takuro
T
Mizukami
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.
Hidetoshi
H
Hayashi
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.
Kazuko
K
Sakai
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.
Marco A
MA
de Velasco
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.
Shuta
S
Tomida
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.
Yoshihiko
Y
Fujita
Department of Surgery, Faculty of Medicine, Kinki University, Osaka, Japan.
Tadao
T
Tokoro
Department of Pathology, Faculty of Medicine, Kinki University, Osaka, Japan.
Akihiko
A
Ito
Department of Surgery, Faculty of Medicine, Kinki University, Osaka, Japan.
Kiyotaka
K
Okuno
Department of Genome Biology, Faculty of Medicine, Kinki University, Osaka, Japan.
Kazuto
K
Nishio
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D019073:HT29 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D009154:Mutation; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000378:metabolism; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012189:Retrospective Studies; D051901:Smad4 Protein / Q000235:genetics*; D055815:Young Adult
C555337:APC protein, human; D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C117307:KRAS protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D016283:Proto-Oncogene Proteins p21(ras)
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation; SMAD family member 4 (SMAD4) mutation; adenomatous polyposis coli (APC) mutation; colorectal mucinous adenocarcinoma; histological grading; next-generation sequencing