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Detection of KRAS Codon 12 Mutations is not Associated with Concurrent Detection of TP53 Mutations in Patients With Rectal Cancer
ASSOCIATION FOR ACADEMIC SURGERY AND SOCIETY OF UNIVERSITY SURGEONS—ABSTRACTS of apoptosis, which is the predominate mode of hepatocellular death from IRI. the goal of the present study was to investigate the role of BH3-only proteins in IRI utilizing a murine model of diet-induced hepatic steatosis. Methods: Male Bim/Bid wild type (WT) and double knockout (dko) mice were fed a high-fat diet (HFD; 60% kilocalories from fat; D12492, Research Diets) ad libitum. After 5 weeks, each animal underwent 60 minutes of 70% warm hepatic ischemia followed by 6 hours of reperfusion. Animals were then sacrificed to collect serum and hepatic tissue for transaminase and triglyceride (TG) content, respectively. Lean controls fed standard chow provided baselines to assess for the development of steatosis and its effect on IRI in both WT and dko mice. Data were analyzed using student’s t-test and reported as mean 6SEM. P value 0.05 was considered significant. Results: Following 5 weeks of HFD, both groups had increased hepatic TG levels (WT: 59.5 69.1 mg/mg protein; dko: 61.9 612.8 mg/mg protein) compared to their lean controls (WT: 31.8 61.5 mg/mg protein; dko: 37.2 63.4 mg/mg protein). the difference in the degree of steatosis between WT and dko mice fed HFD was insignificant (p ¼ 0.89). Steatotic WT mice suffered significantly greater IRI compared to their lean counterparts (p ¼ 0.044 and 0.042 for AST and ALT, respectively) Figure 1. Absence of Bim/Bid proteins significantly attenuated IRI in the setting of steatosis (p ¼ 0.031 and 0.028 for AST and ALT, respectively). in steatotic dko mice, IRI was comparable to lean WT mice (p ¼ 0.285 and 0.502 for AST and ALT, respectively). Conclusions: A murine model of hepatic steatosis is inducible through dietary modification. Hepatic steatosis accentuates IRI. in absence of BH3-only proteins, the accentuation of IRI caused by steatosis is mitigated to levels comparable with lean mice. BH3-only proteins are significant mediators of IRI in the setting of steatosis and may represent novel targets for ameliorating IRI.
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neoadjuvant chemoradiation (CRT). Here, our objective was to determine the incidence of specific KRAS gene mutations with concurrent TP53 gene mutations. Methods: Two hundred patients with AJCC Stage I-III rectal cancer from two prospective clinical trials were assessed. Pre-treatment tumor biopsies were obtained via endoscopy during initial clinical evaluation. Tumor DNA was extracted and KRAS and TP53 mutation status was determined by PCR and sequencing. All patients then underwent preoperative chemotherapy followed by radiation; and then followed by surgery. Response was evaluated according to AJCC guidelines. Surgical specimens without residual disease were determined to have a pathologic complete response (pCR). Results: Overall, 107 (53.5%) patients had TP53 gene mutation, and 73 (36.5%) had KRAS gene mutation; 33 (16.5%) patients had concurrent TP53 and KRAS mutation. Patients with concomitant TP53 and KRAS mutations had the lowest pCR rate when compared to patients with single mutations or wild-type TP53 and KRAS genes(9.1% vs. 35.3%; p¼0.002). We then assessed the codon locations of KRAS mutation and discovered that mutations in codon 12 occurred in 49 (24.5%) patients, codon 13 in 14 (7%) patients, and codon 61 in 7 (3.5%) patients. Patients with codon 12 mutations were less likely to have concurrent TP53 gene mutation compared to patients with either KRAS codon 13 or 61 mutations (38.8% vs. 66.6%; p¼0.0211). Conclusions: Our study confirms that tumors with both KRAS and TP53 mutations are less likely to respond to CRT. in addition, our data suggests that tumors with KRAS codon 12 mutation are less likely to occur with TP53 gene mutation. the association of select genetic alterations may affect tumor response to neoadjuvant therapy.
TABLE 1 Correlation of KRAS and TP53 Gene Mutations Factors
Total
Total Population 200 KRAS Status Wild-type 127 Any KRAS Mutation 73 Codon 12 Mutations 49 Codon 13 or 61 21 Mutations
Wild-type TP53 Mutant TP53 N (%) N (%) p-value 93 (46.5%)
107 (53.5%)
53 (41.7%) 40 (54.8%) 30 (61.2%) 7 (33.3)
74 (58.3%) 33 (45.2%) 19 (38.8%) 14 (66.6%)
0.0795 0.0211 0.2504
39.2. Gastrointestinal Cancers in Young Survivors of Lymphoma: Implications for Earlier Screening. L. R. Smith, E. Feliberti, R. Perry; Eastern Virginia Medical School, Norfolk, VA 38.10. Columbian Surgical Society - Unplanned Reoperations in General Surgery: Risk Factors and Outcomes. O. Guevara
ONCOLOGY 5: COLORECTAL 39.1. Detection of KRAS Codon 12 Mutations is not Associated with Concurrent Detection of TP53 Mutations in Patients With Rectal Cancer. M. N. Duldulao, K. Choy, E. M. Ko, K. Carter, W. Lee, W. Li, Z. Chen, J. Kim, J. GarciaAguilar; City of Hope National Medical Center, Duarte, CA Introduction: We have previously shown that rectal cancer patients with both TP53 and KRAS gene mutations are resistant to
Introduction: Survivors of lymphomas are at greater risk for developing various malignancies later in life. This study sought to determine if patients diagnosed under the age of 40 would benefit from earlier screening for gastrointestinal (GI) malignancies. Methods: Analysis of the Surveillance Epidemiology and End Results (SEER) database using data accrued from 1973-2008. Patients younger than 40 years old who were diagnosed with Hodgkin’s (HL) or Non-Hodgkin’s Lymphoma (NHL) between 1973 and 1993 were included. the incidence of various GI cancers in these patients was obtained. Standardized incidence ratios using the SEERStat software were generated to identify more frequent and early age-onset second malignancies in this cohort. Results: In this time period, 27,339 HL patients and 138,474 NHL patients were identified, among whom 8,892 HL and 7,606 NHL patients were less than 40 years old. Their average age and race were similar but there were more males in the NHL group (54% vs 68%). The 5-year survival among HL and NHL
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neoadjuvant chemoradiation (CRT). Here, our objective was to determine the incidence of specific KRAS gene mutations with concurrent TP53 gene mutations. Methods: Two hundred patients with AJCC Stage I-III rectal cancer from two prospective clinical trials were assessed. Pre-treatment tumor biopsies were obtained via endoscopy during initial clinical evaluation. Tumor DNA was extracted and KRAS and TP53 mutation status was determined by PCR and sequencing. All patients then underwent preoperative chemotherapy followed by radiation; and then followed by surgery. Response was evaluated according to AJCC guidelines. Surgical specimens without residual disease were determined to have a pathologic complete response (pCR). Results: Overall, 107 (53.5%) patients had TP53 gene mutation, and 73 (36.5%) had KRAS gene mutation; 33 (16.5%) patients had concurrent TP53 and KRAS mutation. Patients with concomitant TP53 and KRAS mutations had the lowest pCR rate when compared to patients with single mutations or wild-type TP53 and KRAS genes(9.1% vs. 35.3%; p¼0.002). We then assessed the codon locations of KRAS mutation and discovered that mutations in codon 12 occurred in 49 (24.5%) patients, codon 13 in 14 (7%) patients, and codon 61 in 7 (3.5%) patients. Patients with codon 12 mutations were less likely to have concurrent TP53 gene mutation compared to patients with either KRAS codon 13 or 61 mutations (38.8% vs. 66.6%; p¼0.0211). Conclusions: Our study confirms that tumors with both KRAS and TP53 mutations are less likely to respond to CRT. in addition, our data suggests that tumors with KRAS codon 12 mutation are less likely to occur with TP53 gene mutation. the association of select genetic alterations may affect tumor response to neoadjuvant therapy.
TABLE 1 Correlation of KRAS and TP53 Gene Mutations Factors
Total
Total Population 200 KRAS Status Wild-type 127 Any KRAS Mutation 73 Codon 12 Mutations 49 Codon 13 or 61 21 Mutations
Wild-type TP53 Mutant TP53 N (%) N (%) p-value 93 (46.5%)
107 (53.5%)
53 (41.7%) 40 (54.8%) 30 (61.2%) 7 (33.3)
74 (58.3%) 33 (45.2%) 19 (38.8%) 14 (66.6%)
0.0795 0.0211 0.2504
39.2. Gastrointestinal Cancers in Young Survivors of Lymphoma: Implications for Earlier Screening. L. R. Smith, E. Feliberti, R. Perry; Eastern Virginia Medical School, Norfolk, VA 38.10. Columbian Surgical Society - Unplanned Reoperations in General Surgery: Risk Factors and Outcomes. O. Guevara
ONCOLOGY 5: COLORECTAL 39.1. Detection of KRAS Codon 12 Mutations is not Associated with Concurrent Detection of TP53 Mutations in Patients With Rectal Cancer. M. N. Duldulao, K. Choy, E. M. Ko, K. Carter, W. Lee, W. Li, Z. Chen, J. Kim, J. GarciaAguilar; City of Hope National Medical Center, Duarte, CA Introduction: We have previously shown that rectal cancer patients with both TP53 and KRAS gene mutations are resistant to
Introduction: Survivors of lymphomas are at greater risk for developing various malignancies later in life. This study sought to determine if patients diagnosed under the age of 40 would benefit from earlier screening for gastrointestinal (GI) malignancies. Methods: Analysis of the Surveillance Epidemiology and End Results (SEER) database using data accrued from 1973-2008. Patients younger than 40 years old who were diagnosed with Hodgkin’s (HL) or Non-Hodgkin’s Lymphoma (NHL) between 1973 and 1993 were included. the incidence of various GI cancers in these patients was obtained. Standardized incidence ratios using the SEERStat software were generated to identify more frequent and early age-onset second malignancies in this cohort. Results: In this time period, 27,339 HL patients and 138,474 NHL patients were identified, among whom 8,892 HL and 7,606 NHL patients were less than 40 years old. Their average age and race were similar but there were more males in the NHL group (54% vs 68%). The 5-year survival among HL and NHL