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The Prognostic Significance of KRAS and BRAF Mutation Status In Won et al. BMC Cancer (2017) 17:403 DOI 10.1186/s12885-017-3381-7 RESEARCHARTICLE Open Access The prognostic significance of KRAS and BRAF mutation status in Korean colorectal cancer patients Daeyoun David Won1, Jae Im Lee2, In Kyu Lee1, Seong-Taek Oh2, Eun Sun Jung3 and Sung Hak Lee3* Abstract Background: BRAF and KRAS mutations are well-established biomarkers in anti-EGFR therapy. However, the prognostic significance of these mutations is still being examined. We determined the prognostic value of BRAF and KRAS mutations in Korean colorectal cancer (CRC) patients. Methods: From July 2010 to September 2013, 1096 patients who underwent surgery for CRC at Seoul St. Mary’s Hospital were included in the analysis. Resected specimens were examined for BRAF, KRAS, and microsatellite instability (MSI) status. All data were reviewed retrospectively. Results: Among 1096 patients, 401 (36.7%) had KRAS mutations and 44 (4.0%) had BRAF mutations. Of 83 patients, 77 (92.8%) had microsatellite stable (MSS) or MSI low (MSI-L) status while 6 (7.2%) patients had MSI high (MSI-H) status. Patients with BRAF mutation demonstrated a worse disease-free survival (DFS, HR 1.990, CI 1.080–3.660, P =0. 02) and overall survival (OS, HR 3.470, CI 1.900–6.330, P < 0.0001). Regarding KRAS status, no significant difference was noted in DFS (P = 0.0548) or OS (P = 0.107). Comparing the MSS/MSI-L and MSI-H groups there were no significant differences in either DFS (P = 0.294) or OS (P = 0.557). Conclusions: BRAF mutation, rather than KRAS, was a significant prognostic factor in Korean CRC patients at both early and advanced stages. The subgroup analysis for MSI did not show significant differences in clinical outcome. BRAF should be included in future larger prospective biomarker studies on CRC. Keywords: BRAF mutation, KRAS mutation, MSI, Colorectal cancer Background Network accomplished the largest comprehensive Colorectal cancer (CRC) is the second most common molecular analysis of CRC to date [4]. Based on somatic cancer in females and the third most common cancer in mutation rates, colorectal adenocarcinomas were males worldwide [1]. It is one of the most rapidly growing classified as hypermutated or non-hypermutated. The cancers in Korea with an annual increase (from 1999 to hypermutated group had somatic mutations caused by 2009) of 6.2% in men and 6.8% in women [2]. Despite high microsatellite instability (MSI), usually with MLH1 advances in CRC treatment and a decline in the mortality silencing or mismatch repair gene mutations. BRAF and rate over the past few decades, CRC remains the second ACVR2A mutations were enriched in hypermutated sam- most common cause of cancer death in females and third ples. However, the non-hypermutated group had frequent common cause of cancer death in males [3]. gene copy number alterations. In addition, APC, TP53, Considerable advances have been made in the KRAS,andPIK3CA mutations were observed. These are characterization of genetic alterations in CRC in support characteristic of chromosomal instability [4]. of genome-wide profiling. The Cancer Genome Atlas The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), a member of the Ras subfamily, is a * Correspondence: [email protected] proto-oncogene that encodes a 21 kDa GTPase located 3Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, on the short arm of chromosome 12 [5]. The RAS pro- Seoul 06591, Republic of Korea tein activates several downstream signaling cascades Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Won et al. BMC Cancer (2017) 17:403 Page 2 of 12 such as the mitogen-activated protein kinase (MAPK) stage III CRC patients. According to the BRAF and KRAS and PI3K pathways that regulate multiple cellular func- mutational status, patients were offered targeted agents as tions including cell proliferation, differentiation, motility, an adjunct to systemic chemotherapy. However, due to survival, and intracellular trafficking [6]. KRAS is consid- insurance coverage issues, only 3 patients received anti- ered a key downstream component of the epidermal EGFR and only 12 received anti-vascular endothelial growth factor receptor (EGFR) signaling pathway; there- growth factor therapy during the study period. Approval fore, mutations of the gene result in a constitutive activa- for this study was acquired from the Institutional Review tion of the EGFR signaling cascade [5]. KRAS mutations Board of the Catholic University of Korea, College of are identified in 30–50% of CRCs and are usually point Medicine (KC16RISI0011). mutations that occur in codons 12 and 13, less often in codon 61, and very infrequently at other sites such as DNA isolation and analysis of KRAS and BRAF mutations codons 59, 146, 19, or 20 [5, 7]. KRAS mutation is a well- For DNA isolation, 10-μm-thick sections from formalin- established biomarker that predicts resistance to therapy fixed paraffin-embedded (FFPE) tissue samples were used using anti-EGFR monoclonal antibodies in metastatic for each case. Hematoxylin & eosin sections were used as a CRC [8]. However, the prognostic value of KRAS muta- reference and the largest tumor area was scraped off with a tions in CRC is controversial. Some studies revealed that scalpel under a dissecting microscope. Genomic DNA was KRAS mutations are associated with poorer prognosis, extracted using the QIAamp DNA FFPE tissue kit (Qiagen while others have reported no association [9–12]. Inc., Valencia, CA) according to the manufacturer’s recom- The v-Raf murine sarcoma viral oncogene homolog B1 mendations. Sanger sequencing was performed using an (BRAF) is a serine/threonine kinase that plays a part in cell ABI 3730 automated sequencer (Applied Biosystems, Inc., proliferation, survival, and differentiation; [13]. Activating Foster City, CA), to detect the presence of KRAS exon 2 BRAF mutations have been detected in various malignant mutations with previously reported primers [21]. Exon 15 tumors such as melanoma, papillary thyroid cancer, CRC, of the BRAF gene was amplified by polymerase chain ovarian cancer, and hairy cell leukemia [13–15]. In CRC, reaction (PCR) using the following forward primer (5′- BRAF mutations are reported in 4.7 to 20% of tumors [13, AATGCTTGCTCTGATAGGAAAAT-3′)andreverse 16]. Usually, BRAF and KRAS mutations are usually mutu- primer (5′-TAATCAGTGGAAAAATAGCCTC-3′), result- ally exclusive [17]. The most common BRAF mutation, ing in a 209 base pair PCR product. The resultant PCR found in over 90% of human cancers, is a glutamic acid for products were purified using the QIAquick PCR Purifica- valine substitution at codon 600 in exon 15 (V600E), leading tion Kit (Qiagen Inc., Valencia, CA) and the appropriate to constitutive activation of the MAPK pathway [18]. The protocol on the QIAcube robotic workstation. Each predictive role of BRAF mutation in response to anti-EGFR chromatogram was visually inspected for abnormalities. therapy remains uncertain; however, previous studies found that BRAF mutations are associated with an adverse clinical MSI analysis outcome, especially in advanced stage CRC [16, 19, 20]. Five microsatellite markers (BAT-25, BAT-26, D2S123, In the present study, we comprehensively investigated D5S346, and D17S250) recommended by a National KRAS and BRAF mutation status in Korean CRC patients. Cancer Institute workshop on MSI determined the micro- In addition, we analyzed the relationship of KRAS and satellite status [22]. PCR analyses were performed and the BRAF mutation with MSI status. shift of PCR products from tumor DNA was compared to normal DNA. Tumors with at least 2 of the 5 microsatellite Methods markers displaying shifted alleles were classified as MSI-H, Patients and treatment whereas tumors with only 1 marker exhibiting a novel band We retrospectively reviewed specimens from 1096 con- were classified as MSI-L. Samples in which all microsatellite secutive patients who underwent surgical CRC resection markers displayed the same patterns in tumor and normal at Seoul St. Mary’s Hospital, The Catholic University of tissues were classified as MSS; subsequently, MSS and Korea, between July 2010 and September 2013. CRC cases MSI-L tumors were grouped for analyses based on genetic with tissue blocks eligible for the KRAS and BRAF implications [22]. mutation testing were included in this study. Two gastro- intestinal pathologists reviewed and classified CRC slides Statistical analysis according to World Health Organization classification. Continuous variables were analyzed by student’stor Clinicopathological parameters were obtained from Mann-Whitney U test, expressed as the mean ±SD. For patient medical records and pathology reports at our categorical variables, χ2-test analysis or Fisher’s exact test institution. Adjuvant chemotherapy was recommended to was used. Survival analysis was performed by the high-risk (cancer obstruction, perforation, poor differenti- Kaplan-Meier method. Statistical analysis was performed ation, or lymphovascular/perineural invasion) stage II or with SPSS software version 18 (SPSS Inc., Chicago, IL) Won et al. BMC Cancer (2017) 17:403 Page 3 of 12 and the R programing language (R Core Team 2015, A Impact of KRAS and BRAF mutations on DFS and OS language and environment for statistical computing, R After a median follow-up of 29 months, the 5-year disease Foundation for Statistical Computing, Vienna, Austria, free survival rate of the study population was 81%.
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