Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features.
KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O(6)-methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wild-type carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; P<0.001), demonstrated mucinous differentiation (46 vs 31%; P=0.001) and were associated with different MSI status (P<0.001) and with MGMT methylation (47 vs 21%; P=0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P=0.001), mucinous differentiation (46 vs 25%; P<0.001), presence of a contiguous polyp (38 vs 22%; P<0.001), MGMT methylation (47 vs 26%; P=0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P=0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P=0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.
Cancer and Population Studies Group, Queensland Institute of Medical Research, Herston, Queensland, Australia. c.rosty@uq.edu.au
Christophe
C
Rosty
Joanne P
JP
Young
Michael D
MD
Walsh
Mark
M
Clendenning
Rhiannon J
RJ
Walters
Sally
S
Pearson
Erika
E
Pavluk
Belinda
B
Nagler
David
D
Pakenas
Jeremy R
JR
Jass
Mark A
MA
Jenkins
Aung Ko
AK
Win
Melissa C
MC
Southey
Susan
S
Parry
John L
JL
Hopper
Graham G
GG
Giles
Elizabeth
E
Williamson
Dallas R
DR
English
Daniel D
DD
Buchanan
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D002454:Cell Differentiation; D016009:Chi-Square Distribution; D003111:Colonic Polyps / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000032:analysis / Q000235:genetics; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012307:Risk Factors; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics; D014739:Victoria; D018631:ras Proteins / Q000235:genetics*
D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes