BackgroundKRAS mutations are frequently found in colorectal cancer (CRC) indicating the importance of its genotyping in the study of the molecular mechanisms behind this disease. Although major advances have occurred over the past decade, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role.MethodsThe profile of KRAS mutations in the Brazilian population was analyzed by conducting direct sequencing of KRAS codons 12 and 13 belonging to 8,234 metastatic CRC patient samples. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. The data obtained was analysed comparing different geographical regions, gender and age.ResultsThe median age was 59 years and the overall percentage of wild-type and mutated KRAS was 62.8% and 31.9%, respectively. Interestingly, different percentages of mutated KRAS patients were observed between male and female patients (32.5% versus 34.8%, respectively; p = 0.03). KRAS Gly12Asp mutation was the most prevalent for both genders and for most regions, with the exception of the North where Gly12Val was the most frequent mutation found.ConclusionsTo the best of our knowledge this is one of the largest cohorts of KRAS genotyping in CRC patients and the largest to indicate a higher incidence of KRAS mutation in females compared to males in Brazil. Nevertheless, further research is required to better address the impact of gender differences in colorectal cancer.

e15017 Background: KRAS mutation is common event in colorectal cancer occurring in around 40% of the patients. It is well- known that patients harboring the KRAS mutation do not derive benefit from cetuximab. However data available KRAS mutation profile is limited to Caucasian and Asian individuals and there is a lack of data in the population from Latin America. Brazilian population has a heterogeneous genetic background and this may have pharmacogenetic implications (Suarez-Kurtz, 2006). Methods: Between July and November 2008, we analyzed 989 consecutive patient samples sent to our laboratory for KRAS genotyping as a screening for cetuximab use. DNA was extracted from paraffin-embedded tissue, exons 1 were amplified by PCR and submitted to automatic sequencing. Codons 12 and 13 were analyzed. Results: The median age was 59 years and 53% of the patients were male and 47% female. The percentage of wild-type and mutated KRAS was 62 and 38%, respectively. Among the 375 mutated cases, 87% were in codon 12 versus 13% in codon 13. Mutation Gly12Asp was the most common being detected in 39% of the mutated cases. Due to the sample size a comparison among patients from different regions of Brazil was possible. However, no significant difference was observed in relation to the type or percentage of patients harboring the KRAS mutation. Interestingly, a significant difference in the percentage of mutated KRAS patients was observed between male and female (41 versus 35%, p= 0.05). Conclusions: The profile of KRAS mutation in the Brazilian population is similar to that reported for Caucasian and Asian populations. This is one of the largest cohorts of KRAS genotyping in colorectal cancer patients ever reported. To the best of our knowledge our data is the first to put forward the issue of a potential difference in the mutation rate according to gender. The observed higher incidence of KRAS-mutation in male than female deserves further investigation. No significant financial relationships to disclose.

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e14101 Background: Although major advances in the last decades, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role. Some groups, including ours, observed that KRAS mutation may be more frequent in female than male (Ferreira C.G. et al. J Clin Oncol 28: 2010 suppl abstr 3614; Uetake H. et al. J Clin Oncol 29: 2011 suppl abstr 3605). Methods: Between July 2008 and July 2011, we analyzed 8,234 consecutive patient samples sent to a reference laboratory for KRAS genotyping as a screening for cetuximab use. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. Codons 12 and 13 were analyzed. Results: The median age was 59 years and well balanced according to gender with 51.9% of male and 48.1% female patients. The percentage of wild-type and mutated KRAS was 66.4 and 33.6%, respectively. Corroborating previous findings a significant difference in the percentage of mutated KRAS patients was observed between female and male (34.8% versus 32.5%, p = 0.03). However there were no differences in the distribution of any specific KRAS mutation according to gender. Among the 2,626 mutated cases, 83% were in codon 12 versus 17% in codon 13. Mutation Gly12Asp was the most common being detected in 36% of the mutated cases. Conclusions: This is one of the largest cohorts of KRAS genotyping in CRC patients. In line with previous data our present findings indicate that KRAS-mutations are more frequent in female than male. Further research is required to better address the impact of gender differences and/or hormones as potential drivers of CRC carcinogenesis.

Personalised medicine is an evolving field that seeks to target cancer therapies based on unique genetic characteristics of the tumour and/or the patient. One of the most significant advances towards personalised care in the field of oncology was the establishment of KRAS gene mutation as a validated biomarker predicting efficacy in epidermal growth factor receptor (EGFR) targeted therapies in the treatment of metastatic colorectal cancer (mCRC). KRAS mutations are frequently found in CRC indicating the importance of its genotyping in the study of the molecular mechanisms behind this disease. Although major advances have occurred over the past decade, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role. Therefore, in this study the profile of KRAS mutations in the Brazilian population was analysed by conducting direct sequencing of KRAS codons 12 and 13 belonging to 8,234 metastatic CRC patient samples from different Brazilian regions. The median age was 59 years and the overall percentage of wild-type and mutated KRAS was 66.4% and 33.6%, respectively. Interestingly, a significant difference in the percentage of mutated KRAS patients was observed between male and female (32.5% versus 34.8%, p=0.03). However, there were no differences in the distribution of any specific KRAS mutation according to gender. This is one of the largest cohorts of KRAS genotyping in CRC patients indicating a higher incidence of KRAS mutations in females compared to males. Citation Format: Veronica Aran, Fernando M. Vieira, Ana Paula Victorino, Jonas H. Salem, Ilana Zalcberg-Renault, Martin H. Bonamino, Mariano Zalis, Carlos Gil Ferreira. KRAS mutations: Variable incidences in a Brazilian cohort of 8,234 metastatic colorectal cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A58. doi: 10.1158/1557-3125.RASONC14-A58