title: Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma.
abstract: Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G>A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P=0.034) and more frequent pancreatic invasion (P=0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G>A transitions and G12D mutations) were significantly correlated with higher pT classification (P=0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P=0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P=0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wild-type KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients.
authors.affiliation: Department of Pathology, Incheon St. Mary's Hospital, The Catholic University of Korea, Incheon, Republic of Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Jun
authors.affiliation: Department of Pathology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea.
authors.forename: Misung
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yeungnam University College of Medicine, Daegu, Republic of Korea.
authors.forename: Mi
authors.initials: M
authors.lastname: Jin Gu
authors.affiliation: Department of Pathology, Yeungnam University College of Medicine, Daegu, Republic of Korea.
authors.forename: Young
authors.initials: Y
authors.lastname: Kyung Bae
authors.affiliation: Department of Pathology, Kosin University College of Medicine, Busan, Republic of Korea.
authors.forename: Hee-Kyung
authors.initials: HK
authors.lastname: Chang
authors.affiliation: Department of Pathology, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun
authors.initials: E
authors.lastname: Sun Jung
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Kee-Taek
authors.initials: KT
authors.lastname: Jang
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jihun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eunsil
authors.initials: E
authors.lastname: Yu
authors.affiliation: Department of Pathology, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea.
authors.forename: Dae
authors.initials: D
authors.lastname: Woon Eom
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seung-Mo
authors.identifier: http://orcid.org/0000-0002-8888-6007
authors.initials: SM
authors.lastname: Hong
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007421:Intestine, Small / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)