K-RAS mutations in colorectal cancer in patients from Podlaskie region

2016 ◽  
Vol 6 (1) ◽  
pp. 70-77
Author(s):  
M. Chomczyk ◽  
P. Czajka
Keyword(s):  
Colorectal Cancer ◽  
Genetic Predisposition ◽  
Tumor Development ◽  
Tumor Differentiation ◽  
Gene Encoding ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Ras Protein ◽  
Study Population ◽  
Medical University

Introduction: In Poland, colorectal cancer is the second leading cause of death. The incidence of colorectal cancer increases with age and early onset indicates and increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patients age, gender, sex and morphological factors are unknown in Podlaskie region, Poland. Materials and methods: We investigated seventy five patients (43 men and 32 women) who underwent surgery for cancer of the colorectal in the II Department of General and Gastroenterological Surgery, Medical University of Białystok in 2002- 2007. The average age of patients was 64.8 years (the average age of women 66.7, men 63.1). All patients for the study of molecular research (absence or presence of K-RAS mutations) had histopathology confirmed adenocarcinoma. Results: There was no correlation presence or absence of mutations in K-RAS of the following clinical and morphological factors: gender, age, location, degree of tumor differentiation, tumor size and metastases to lymph nodes and other organs The gene encoding the K-Ras protein is mutated in 20- 50% of cases of colorectal cancer. Such a difference of results is influenced by several factors: differences of the techniques used for detecting mutations, differences in codon of the gene that is considered codon 12 and /or 13 and / or 61 and differences in the selection and study population. Conclusions: These data suggest the clinical and morphological factors in patients with colorectal cancer have no effect on the presence of K-RAS. mutation.

Using low sensitivity of direct sequencing to detect K-ras mutations? A new method for improving diagnostic accuracy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22100-e22100
Author(s):  
Chi-Kuan Chen
Keyword(s):  
Colorectal Cancer ◽  
Real Time ◽  
Cancer Patients ◽  
Real Time Pcr ◽  
Mutation Detection ◽  
Direct Sequencing ◽  
Standard Procedure ◽  
Ras Gene ◽  
Ras Mutation ◽  
Ras Mutations

e22100 Background: Identifying K-ras mutation has became a standard procedure in cancer treatment. Colorectal cancer patients with K-ras mutation are likely to poorly respond to cetuximab. Therefore, detecting K-ras gene mutations should be suggested before the selection of personalized treatment in colorectal cancer. To date, general molecular biology techniques contain HRM, PCR-RFLP, TaqMan PCR and CE-IVD-validated Cobas 4800 KRAS (Roche Diagnostics) are used for K-ras mutation detection in molecular diagnosis, but the sensitivity limitation of these method is approximately 1%. Methods: Therefore, we used a new approach, a universal genetic detecting method (FemtoPath), which improves sensitivity of K-ras mutation detection and the limitation of sensitivity is closed to 0.1% of mutation type. Results: We compared the sensitivity between FemtoPath/direct sequencing test and Cobas KRAS real-time PCR. Cobas real-time PCR identifies mutations in 21 (40.38%) of the 52 tumors. Surprisingly, the FemtoPath/direct sequencing test identified mutations in 40 (76.92%) of the 52 tumors. Our data showed that the FemtoPath/direct sequencing test can identify 19 additional mutation samples. In addition, the FemtoPath/direct sequencing test can identify more unknown K-ras mutations adjacent to codon 12 and 13. Conclusions: Ensure the most timely and appropriate therapy for cancer patients is the first priority of clinical application. FemtoPath/direct sequencing test is more sensitive, accurate and inexpensive and needs fewer sample amount than Cobas real-time PCR.

RAS Mutations in Circulating Tumor DNA and Clinical Outcomes of Rechallenge Treatment With Anti-EGFR Antibodies in Patients With Metastatic Colorectal Cancer

2020 ◽  
pp. 898-911
Author(s):  
Yu Sunakawa ◽  
Masato Nakamura ◽  
Masahiro Ishizaki ◽  
Masato Kataoka ◽  
Hironaga Satake ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Clinical Outcomes ◽  
Circulating Tumor Dna ◽  
Wild Type ◽  
Phase Ii Trials ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Ras Status ◽  
Tumor Dna

PURPOSE Several trials have evaluated the efficacy of rechallenge treatment with anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with metastatic colorectal cancer (mCRC). A recent trial indicated that RAS status in circulating tumor DNA (ctDNA) may potentially predict patients with RAS wild-type mCRC resistant to anti-EGFR mAb who would benefit from rechallenge treatment, and the findings should be further investigated. MATERIAL AND METHODS We enrolled patients whose plasma samples were collected in prospective phase II trials, the JACCRO CC-08 (n = 36) and CC-09 (n = 25), which evaluated rechallenge chemotherapy with anti-EGFR mAb for KRAS wild-type mCRC. RAS in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC kit. RESULTS Sixteen patients were enrolled in this study, with a response rate of 0% and a disease control rate (DCR) of 62.5%. RAS mutations were found at baseline in six patients. The DCR was 33% in patients with RAS mutations in ctDNA, whereas it was 80% in patients without RAS mutation at baseline. Patients with RAS mutation at baseline had significantly shorter progression-free survival (PFS) and overall survival (OS) than those without RAS mutation (median PFS, 2.3 v 4.7 months; hazard ratio [HR], 6.2; P = .013; median OS, 3.8 v 16.0 months; HR, 12.4; P = .0028). Six of 10 patients without RAS mutation at baseline acquired RAS mutations at progression. Postprogression survival after rechallenge treatment was numerically shorter in patients with RAS mutation at progression. CONCLUSION RAS status in ctDNA was significantly associated with clinical outcomes in patients with mCRC receiving rechallenge treatment with anti-EGFR mAb. These findings could support the clinical utility of OncoBEAM RAS CRC kits for anti-EGFR mAb rechallenge in RAS wild-type mCRC.

Association of RAS mutations with race in metastatic colorectal cancer: CALGB/SWOG 80405 (ALLIANCE).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 638-638 ◽  
Author(s):  
Amikar Sehdev ◽  
Donna Niedzwiecki ◽  
Alan P. Venook ◽  
Heinz-Josef Lenz ◽  
Federico Innocenti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Multivariate Analysis ◽  
Adjuvant Chemotherapy ◽  
Multivariate Analyses ◽  
Exon 2 ◽  
Ras Mutation ◽  
Pelvic Radiation ◽  
Ras Mutations ◽  
Mutational Status ◽  
Significant Difference

638 Background: Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular subtypes in part based on RAS mutational status. It is plausible that RAS mutations are differentially distributed between CC and AA and may contribute to poor outcomes in AAs with CRC. Methods: We did a retrospective analysis of CALGB/SWOG 80405 trial patients. We divided the entire cohort into 2 groups: a) Common RAS: mutation in KRAS exon 2, codon 12 or 13; b) Extended RAS: any NRAS mutations or mutation in KRAS except those listed above. We then analyzed these two subgroups for association between RAS mutations and race (3 categories: Caucasian, AA, Others) using chi-square test for univariate analyses and logistic regression for multivariate analysis. We also analyzed the effect of extended RAS testing on prognosis of metastatic CRC by estimating the overall survival (OS) using Kaplan-Meier method and 95% confidence interval (CI). Cox proportional-hazard model was used for multivariate analyses. Results: There were 1729 CRC patients in common RAS group of which 357 (20.6%) had mutations present. Extended RAS group had 621 patients of which 95 (15.5%) had mutations present. There was no significant difference in the rate of common RAS mutations between CC and AA (20.5% vs. 24%, p=0.22). However, extended RAS mutations were significantly more in AA as compared to CC (25% vs. 14%, p=0.02). Multivariate analysis adjusted for age, gender, prior adjuvant chemotherapy and pelvic radiation confirmed higher odds of extended RAS mutation in AA compared to CC (adjusted OR 1.12; 95% CI 1.01-1.23; p=0.02). The median OS in patients with an extended RAS mutation was shorter as compared to those without extended RAS mutation (25.3 vs. 31.9 months; HR 1.26; 95% CI 0.99-1.62; p=0.05). Multivariate analyses adjusted for age, gender, race, prior adjuvant chemotherapy and pelvic radiation showed a trend towards longer OS in patients without extended RAS mutation as compared those with extended RAS mutation (adjusted HR= 1.24, 95% CI, 0.97-0.1.58, p=0.08). Conclusions: Extended RAS mutations are significantly more common in AA as compared to CC. Additionally, presence of extended RAS mutation may confer a poor prognosis in CRC patients.

scholarly journals Association of RAS mutations with early progression after first-line systemic therapy in patients with initially unresectable colorectal cancer liver metastasis

2021 ◽  
Author(s):  
Di Cao ◽  
Cong Li ◽  
Chi Zhou ◽  
Weili Zhang ◽  
Zhenhai Lu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Factor ◽  
Disease Progression ◽  
Systemic Therapy ◽  
Driver Gene ◽  
First Line ◽  
Early Disease ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Early Progression

Abstract Purpose Patients with initially unresectable colorectal cancer with liver metastases (IU-CRLM) need to undergo first-line systemic therapy with the aid of chemotherapy. However, the driver gene attributed to early progression in IU-CRLM patients after first-line systemic therapy remains unclear. Our study explored the RAS mutation status related to early progression in IU-CRLM patients. Methods A total of 193 IU-CRLM patients with RAS status detection were retrospectively enrolled from December 2012 to January 2020. We defined early progression as tumour progression within 6 months after first-line systemic therapy. Univariate and multivariate logistic regression for early progression were implemented to identify the risk factors. Results RAS mutations were found in 51 (26.0%) IU-CRLM patients. A total of 107 (55.4%) patients were confirmed to have early progression after first-line systemic therapy. RAS mutation was significantly related to early disease progression (66.7% vs. 49.3%, P=0.033). Logistic analysis results showed that RAS mutation (OR=2.962, 95% CI 1.354-6.478, P=0.007) was an independent risk factor for early disease progression. Conclusions Mutated RAS was an important risk factor for early progression in IU-CRLM patients after first-line systemic therapy.

Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab

2007 ◽  
Vol 25 (22) ◽  
pp. 3230-3237 ◽  
Author(s):  
Shirin Khambata-Ford ◽  
Christopher R. Garrett ◽  
Neal J. Meropol ◽  
Mark Basik ◽  
Christopher T. Harbison ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Expression Profiles ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Epithelial Tumor ◽  
Ras Mutation ◽  
Ras Mutations

Purpose The antiepidermal growth factor receptor (EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab. Patients and Methods One hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies. Results Gene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab (EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations (P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival (PFS) than patients with low expression (EREG: P = .0002, hazard ratio [HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively). Conclusion Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.

Clinical applications of extended ctDNA RAS mutation determination in metastatic colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 607-607
Author(s):  
Joana Vidal Barrull ◽  
Laura Muinelo ◽  
Alba Dalmases ◽  
Alicia Abalo ◽  
Maria Carmen Vela ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Ct Scan ◽  
Response To Treatment ◽  
Plasma Samples ◽  
Ras Mutation ◽  
Mutation Status ◽  
Ras Mutations ◽  
Detection Techniques ◽  
Anti Vegf

607 Background: Tumor tissue is currently used for RAS testing in metastatic colorectal cancer (mCRC) patients, but detection of circulating tumor (ct) DNA in plasma is being actively investigated as an alternative for detection and monitoring RAS mutations during therapy. Methods: Concordance of RAS testing in plasma using the OncoBEAM RAS CRC test and RAS testing in tissue using standard-of-care RAS detection techniques was evaluated in 114 mCRC antiEGFR-naïve patients. In discordant cases, tissue samples were re-examined by BEAMing. OncoBEAM RAS CRC assay was also used to monitor RAS mutation status in serial plasma samples from 34 patients treated with anti-VEGF +/- chemotherapy or anti-EGFR based therapy. Results: The overall agreement of the two methods was 93% (106/114 patients), with positive agreement of 96.2% (51/53) and negative agreement of 90.2% (55/61). Longitudinal monitoring of plasma samples from 13 patients with RAS mutated tumors treated with chemotherapy +/- anti-VEGF, showed a significant decrease (or disappearance) of RAS mutant allele fraction (MAF) in all cases at the time of CT-scan (8-12 weeks after onset of treatment). In 3 patients, plasma was also analyzed at week 4 showing the same dramatic decrease in MAF. RAS decline mirrored clinical and radiological response to treatment. Interestingly, RAS decline was also observed in patients with stable disease in CT-scan by RECIST1.1. In 7 of 9 patients that subsequently progressed, RAS ctDNA fraction increased accordingly. On the other hand, among 22 patients RAS wt treated with cetuximab, 6 showed emergence of RAS mutations at progression. In two cases, multiple RAS mutations were concomitantly present. Conclusions: The high overall agreement between basal plasma and tissue RAS mutation status indicates that blood-based testing with OncoBEAM RAS CRC is a viable alternative to tissue RAS testing in mCRC patients. Moreover, this study highlights the utility of OncoBEAM RAS CRC to monitor treatment of mCRC patients in two setting: (a) evaluation of response to anti-VEGF +/- chemotherapy in RAS mutant patients, as a complement to RECIST radiological criteria and (b) to monitor emergence of resistant clones during anti-EGFR treatment in RAS wt patients.

Inhibition of rat colon tumors by sulindac and sulindac sulfone is independent of K-ras (codon 12) mutation

2000 ◽  
Vol 278 (2) ◽  
pp. G266-G272 ◽  
Author(s):  
Tanya A. de Jong ◽  
Stewart A. Skinner ◽  
Cathy Malcontenti-Wilson ◽  
Daphne Vogiagis ◽  
Michael Bailey ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Treated Group ◽  
Rat Colon ◽  
Sprague Dawley ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Mechanism Of Inhibition ◽  
Group 5

Nonsteroidal anti-inflammatory drug (NSAID) use reduces the risk of colorectal cancer by 40–50%. Previous studies suggest that effective inhibition of colorectal cancer by NSAIDs may be dependent on the presence or absence of a K-ras mutation. This study was aimed at determining the relationship between inhibition of colorectal cancer by sulindac and sulindac sulfone and the presence of activating K-ras mutations in the 1,2-dimethylhydrazine dihydrochloride rat model. Sulindac (20 mg ⋅ kg−1 ⋅ day−1), sulindac sulfone (40 mg ⋅ kg−1 ⋅ day−1), or vehicle was administered orally to male Sprague-Dawley rats for a 4-wk period beginning 20 wk after tumor induction. Tumor number and volume were measured before treatment by laparotomy and colonoscopy and again after treatment. Sulindac and sulindac sulfone treatment significantly reduced the number and volume of colorectal tumors compared with control rats. For K-ras (codon 12) mutation detection, frozen tumor tissue was collected at the endpoint. We found K-ras codon 12 mutations in 11 of 21 (52%) control tumors. The proportion of tumors with K-ras mutations in the sulindac-treated group [5 of 8 (62%); odds ratio = 1.51 (95% confidence interval = 0.29, 8.33)] and the proportion of sulindac sulfone-treated tumors [9 of 14 (64%); odds ratio = 1.63 (95% confidence interval = 0.41, 6.66)] were not significantly different from controls. Tumor inhibition did not correlate with K-ras (codon 12) mutation status, which suggests that the mechanism of inhibition of rat colorectal cancer by sulindac and sulindac sulfone is independent of K-ras mutation.

Detection of colorectal neoplasia associated K-Ras mutations in human urine

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1005-1005
Author(s):  
D. E. Brenner ◽  
Y. Su ◽  
D. P. Normolle ◽  
S. Syngal ◽  
R. Bresalier ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Human Urine ◽  
Mutation Detection ◽  
Colorectal Neoplasia ◽  
Dna Fragments ◽  
Hyperplastic Polyps ◽  
Training Set ◽  
Ras Mutation ◽  
Ras Mutations ◽  
Ras Genes

1005 Background: Since colorectal neoplasia-associated genes have been detected in human blood, we hypothesized that small DNA fragments containing genetic mutations associated with colorectal neoplasias are filtered and excreted in the urine. If so, genes associated with colorectal cancer will be detected in the urine. K-ras mutations are commonly associated with colorectal neoplasia and do not occur in the urinary tract. Methods: K-ras mutation detection: 200 microl of urine was extracted with guanidine thiocyanate and purifed using a Wizard DNA isolation kit. Codon 12 K-ras mutation detection methods–1: restriction enriched PCR, 20 cycles, with primers that amplify both wild type and mutated DNA but with an artificial BstNI site at the 5’ end of the amplified product (>2 K-ras copies per assay); 2: Peptide nucleic acid clamping real time PCR (>15 K-ras copies per assay). Human subjects: Training set = 20 patients with known K-ras mutations in colorectal cancer tissue. Test set = blinded urine samples from colorectal adenocarcinoma (N=48), adenoma (N=31), hyperplastic polyp (N=12) and endoscopically normal colon and rectum (N=60). Results: 1. Human urine contains 150–250 base pair DNA fragments derived from the circulation. These fragments can be readily distinguished from high molecular weight DNA from sloughed urinary tract cells. 2. Training set for K-ras detection (tissue confirmed K-ras mutations): Serum 6/20 (30%), Plasma (11/20 (55%), Urine: 18/20 (90%), (p<0.15 for plasma, p<0.001 for serum). 3. Test set (blinded): a. >2 copies of mutated K-ras genes were detected in: 16/48 (33%) adenocarcinomas; 23/31 (74%) adenomas; 5/12 (42%) hyperplastic polyps, and 19/60 (31%) non-neoplasia controls. b. >15 copies of mutated K-ras genes were detected in: 12/48 (25%) adenocarinomas; 15/31 (48%) adenomas; 3/12 (25%) hyperplastic polyps, and 11/60 (18%) non-neoplasia controls. Conclusions: Small DNA fragments in human urine contain K-Ras mutations identical to those found in colorectal cancer DNA. The sensitivity for detection of K-ras mutations in urine appears equivalent or superior to K-ras mutation detection in feces or serum. DNA mutations from systemic epithelial neoplasias may be detected in filtered urinary DNA fragments and may be useful for early detection of neoplasia. No significant financial relationships to disclose.

Association between gene fusions and anti-EGFR resistance signature in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
Thereasa A. Rich ◽  
Katherine Clifton ◽  
Victoria M. Raymond ◽  
Arvind Dasari ◽  
Kanwal Pratap Singh Raghav ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Acquired Resistance ◽  
Circulating Tumor Dna ◽  
Egfr Mutations ◽  
Ras Mutation ◽  
Exact Test ◽  
Ras Mutations ◽  
Alk 5 ◽  
Tumor Dna ◽  
Fischer Exact Test

3564 Background: Acquired resistance to anti-EGFR therapy in metastatic colorectal cancer (mCRC) has been characterized by a circulating tumor DNA (ctDNA) signature including any sub-clonal RAS mutation, co-existing RAS mutations, or co-existing EGFR mutations. Here, we investigated if fusions in ctDNA are associated with this anti-EGFR signature for CRC patients (pts). Methods: 4289 advanced stage CRC pts underwent molecular profiling using a plasma-based NGS assay that included FGFR2, FGFR3, RET, ALK, NTRK1, and ROS1 fusions. Available clinical histories were reviewed. Correlations between fusions and clinicopathological features were measured with a Fischer exact test. Relative frequencies of genomic alterations were compared between fusion-present vs -absent cases with an unpaired t-test. Clonality for a given alteration was called for a relative variant allele frequency (rVAF) > 50 %, while subclonal was defined as < 50% rVAF. Results: 44 unique fusions were detected in 40 (1.1%) of the 3808 pts with alterations present: RET (N = 16), FGFR3 (N = 12), ALK (N = 10), NTRK1 (N = 3), ROS1 (N = 2), and FGFR2 (N = 1). Relative to non-fusion variants detected, fusions were more likely to be subclonal (OR 8.2, p < 0.0001). Mutations associated with a previously reported anti-EGFR resistance were found in FGFR3 (7/12 pts), RET (7/15 pts) and ALK (5/10 pts). In fusion-present cases, co-existing RAS mutations were more likely to be subclonal than non-fusion cases (OR 14, p < 0.0001). EGFR mutations were more common in fusion present cases (OR 3.7, p = 0.0001) and predominantly subclonal (97%). EGFR mutations aggregated to ectodomain sites (85%) previously linked to acquired anti-EGFR resistance. For 27 pts with available clinical histories, 21 (78%) received anti-EGFR treatment prior to ctDNA testing. Conclusions: Actionable fusions using a ctDNA NGS assay were predominantly subclonal and co-existed with subclonal RAS and EGFR mutations. These clinicopathologic features are consistent with a previously validated signature linked to resistance to anti-EGFR therapies in CRC. We hypothesize that fusions may arise as a previously undescribed mechanism of acquired resistance to anti-EGFR therapies in CRC pts.

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