KRAS gene mutation in patients with primary colorectal cancer

Objective: KRAS mutation occurs in 30% to 50% of colorectal cancers. The aim of our study was to determine the frequency of KRAS mutations among patients with colorectal cancer; and the relationship with clinicopathologic features. Materials and Methods: 79 colorectal cancer cases at a hospital in Hai Phong of Vietnam were collected, including 45 colon cancer and 34 rectal cancer during January 2010 and July 2012. PCR amplification and DNA sequencing were used to detect mutations in exon 2 of KRAS gene. The study was based on informed consent and approval by the Ethics Committee of Viet Tiep Hospital. Results: KRAS mutation was found in 40.4% (225/557) colorectal cancer. All mutation locations were in codon 12. There was significant association (p < 0.05) between KRAS mutations, tumor size and tumor stage. No significant association was observed between KRAS mutations and gender, tumor location, tumor grade or histologic presence of mucin (p>0.05). Conclusion: Determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers Keywords: colorectal cancer, KRAS gene mutation, clinicopathology.

Download Full-text

INVESTIGATION KRAS MUTATION IN CIRCULATION TUMOR DNA IN DIFFERENT STAGES OF COLORECTAL CANCER

Problems in oncology ◽

10.37469/0507-3758-2019-65-5-701-707 ◽

2019 ◽

Vol 65 (5) ◽

pp. 701-707

Author(s):

Vitaliy Shubin ◽

Yuriy Shelygin ◽

Sergey Achkasov ◽

Yevgeniy Rybakov ◽

Aleksey Ponomarenko ◽

...

Keyword(s):

Colorectal Cancer ◽

Plasma Volume ◽

Kras Mutation ◽

Stage Iv ◽

Circulating Tumor Dna ◽

Stage Ii ◽

Kras Gene ◽

Kras Mutations ◽

Droplet Pcr ◽

Tumor Dna

To determine mutations in the plasma KRAS gene in patients with colorectal cancer was the aim of this study. The material was obtained from 44 patients with colorectal cancer of different stages (T1-4N0-2bM0-1c). Plasma for the presence of KRAS gene mutation in circulating tumor DNA was investigated using digital droplet polymerase chain reaction (PCR). KRAS mutations in circulating tumor DNA isolated from 1 ml of plasma were detected in 13 (30%) patients with cancer of different stages. Of these, with stage II, there were 3 patients, with III - 5 and with IV - 5. Patients who did not have mutations in 1 ml of plasma were analyzed for mutations of KRAS in circulating tumor DNA isolated from 3 ml of plasma. Five more patients with KRAS mutations were found with II and III stages. The highest concentrations of circulating tumor DNA with KRAS mutation were found in patients with stage IV. The increase in plasma volume to 3 ml did not lead to the identification of mutations in I stage. This study showed that digital droplet PCR allows identification of circulating tumor DNA with the KRAS mutations in patients with stage II-IV of colon cancer. The results can be used to determine the degree of aggressiveness of the tumor at different stages of the disease, but not the 1st, and it is recommended to use a plasma volume of at least 3 ml.

Download Full-text

IMPACT OF KRAS MUTATIONS IN CLINICAL FEATURES IN COLORECTAL CANCER

ABCD Arquivos Brasileiros de Cirurgia Digestiva (São Paulo) ◽

10.1590/0102-672020200003e1524 ◽

2020 ◽

Vol 33 (3) ◽

Author(s):

Renato Morato ZANATTO ◽

Gianni SANTOS ◽

Júnea Caris OLIVEIRA ◽

Eduardo Marcucci PRACUCHO ◽

Adauto José Ferreira NUNES ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Kras Mutation ◽

Direct Sequencing ◽

Colorectal Carcinogenesis ◽

Kras Mutations ◽

Primary Tumor Site ◽

Exon 2 ◽

Metastatic Site ◽

Colorectal Cancer Patients

ABSTRACT Background: KRAS mutations are important events in colorectal carcinogenesis, as well as negative predictors of response to EGFR inhibitors treatment. Aim: To investigate the association of clinical-pathological features with KRAS mutations in colorectal cancer patients treated. Methods: Data from 69 patients with colorectal cancer either metastatic at diagnosis or later, were retrospectively analyzed. The direct sequencing and pyrosequencing techniques were related to KRAS exon 2. The mutation diagnosis and its type were determined. Results: KRAS mutation was identified in 43.4% of patients. The most common was c.35G>T (p.G12V), c.35G>A (p.G12D) and c.38G>A (p.G13D). No correlation was found between KRAS mutation and age (p=0.646) or gender (p=0.815). However, mutated group had higher CEA levels at admission (p=0.048) and codon 13 mutation was associated with involvement of more than one metastatic site in disease progression (p=0.029). Although there was no association between primary tumor site and mutation diagnosis (p=0.568), primary colon was associated with worse overall survival (p=0.009). Conclusion: The KRAS mutation was identified in almost half of patients. Mutated KRAS group had higher levels of CEA at admission and the mutation at codon 13 was associated with involvement of more than one metastatic site in the course of the disease. Colon disease was associated with the worst overall survival.

Download Full-text

KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy

Cancers ◽

10.3390/cancers11101514 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1514 ◽

Cited By ~ 5

Author(s):

Ghimessy ◽

Gellert ◽

Schlegl ◽

Hegedus ◽

Raso ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Kras Mutation ◽

Antiangiogenic Therapy ◽

Hazard Ratio ◽

Wild Type ◽

First Line ◽

Kras Mutations ◽

Exon 2 ◽

Mutational Status ◽

Platinum Based Chemotherapy

Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.

Download Full-text

Clinical characteristics and prognostic value of the KRAS mutation in Chinese colorectal cancer patients

The International Journal of Biological Markers ◽

10.1177/17246008211017152 ◽

2021 ◽

pp. 172460082110171

Author(s):

Ye Yuan ◽

Yingting Liu ◽

Ye Wu ◽

Junling Zhang ◽

Chunti Shen ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Cancer Patients ◽

High Frequency ◽

Kras Mutation ◽

Chinese Patients ◽

Wild Type ◽

Kras Mutations ◽

Exon 2 ◽

Colorectal Cancer Patients

Background: The KRAS mutations are high-frequency somatic mutations found in colorectal cancer patients from Western and Asian countries however, with the exception of exon 2 of KRAS, other prevalence and prognostic values have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of whole exon mutations of KRAS in Chinese colorectal cancer patients and to investigate their impact on prognosis. Methods: A total of 7189 tumor tissue samples (iCohort) were subjected to next-generation sequencing for detection of KRAS mutations. All pathologic or likely pathologic mutations of KRAS were considered. In addition, clinical features and prognostic dates were collected from 145 patients at The Third Affiliated Hospital of Soochow University, China (sCohort) and used droplet digital™ polymerase chain reaction to detect KRAS mutations. Results: In the iCohort, 2706 patients (37.6%) were confirmed harboring KRAS mutations. The most frequent of these mutations were G12D (32.19%), G12V (17.96%), and G13D (17.59%). In the sCohort, 51 colorectal cancer patients (35.17%) had KRAS mutations, among which KRAS G12D (64.71%), G13D (29.41%), and G14D (3.92%) were high-frequency. The KRAS mutations were associated with shorter median overall survival than wild-type tumors (69 vs. 55 months; HR 1.80; 95% Cl 1.22, 2.64; P=0.0003). In the Cox multivariate analysis, age (HR 1.562; 95% Cl 1.10, 2.22; P=0.013), tumor differentiation (HR 0.417; 95% Cl 0.19, 0.90; P=0.026), and KRAS mutation (HR 1.897; 95% Cl 0.19, 0.90; P=0.001) remained independent predictors of shorter overall survival. Among the common KRAS mutations, G12D was significantly associated with shorter overall survival (HR 2.17; 95% Cl 1.31, 3.58; P < 0.0001) compared with KRAS wild-type patients. Conclusions: Our findings indicate that KRAS genes are frequently mutated, and over 30% harbored the KRAS G12D mutation subtype. We found that the KRAS G12D mutation is associated with inferior survival and is a biomarker of poor prognosis in Chinese patients. Our data emphasize the importance of molecular features in colorectal cancer patients, which could potentially be improved by G12D-specific related inhibitors.

Download Full-text

Age-dependent prognostic value of KRAS mutation in metastatic colorectal cancer

Future Oncology ◽

10.2217/fon-2021-0650 ◽

2021 ◽

Author(s):

Muhammet Ozer ◽

Suleyman Yasin Goksu ◽

Nina Niu Sanford ◽

Chul Ahn ◽

Muhammad Shaalan Beg ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Kras Mutation ◽

Prognostic Value ◽

Age Groups ◽

Prognostic Impact ◽

Kras Gene ◽

Kras Mutations ◽

Kras Status ◽

Age Dependent

Background: The age-dependent prognostic impact of KRAS status in metastatic colorectal cancer (mCRC) is unknown. Materials & Methods: We used the National Cancer Database to evaluate the survival by KRAS status for age-groups <50, 50–69 and ≥70, adjusting for relevant patient and tumor characteristics. Results: mCRC patients (n = 26,095; 33.5%) had KRAS status reported, and 11,338 of these patients (43.4%) had mutations in the KRAS gene. Patients with KRAS mutations had worse overall survival than wild-type KRAS patients. In age-groups <50 years (23 vs 29 months; p < 0.001) and 50–69 (21 vs 23.4 months; p < 0.001), KRAS mutations were significantly associated with worse survival, whereas in the ≥70-year age-group, there was no significant association (14 vs 14 months; p = 0.34). Conclusion: We conclude that the age of patients influences the prognostic value of KRAS mutation in metastatic colorectal cancer.

Download Full-text

KRAS mutations preclude tumor shrinkage of colorectal cancers treated with cetuximab

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4132 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 4132-4132 ◽

Cited By ~ 8

Author(s):

W. De Roock ◽

J. De Schutter ◽

G. De Hertogh ◽

M. Janssens ◽

B. Biesmans ◽

...

Keyword(s):

Tumor Size ◽

Kras Mutation ◽

Objective Response ◽

Complete Response ◽

Rapid Onset ◽

Colorectal Cancers ◽

Tumor Shrinkage ◽

Kras Mutations ◽

Exon 2 ◽

Early Tumor

4132 Background: A recent study has shown that the presence of a KRAS mutation is associated with the absence of objective response to cetuximab (CTX) in advanced colorectal cancers (mCRC). Our hypothesis was that CTX cannot induce any tumor shrinkage in KRAS mutant mCRC. Methods: We analyzed KRAS exon 2 mutation status by Taqman, PCR and sequencing on 37 available tumor samples from patients with mCRC progressive on chemotherapy. Twenty patients received CTX combined with irinotecan (BOND) and 17 received CTX in monotherapy (7 BOND, 10 SALVAGE). We measured the change in tumor size between baseline and the consecutive evaluations. At week 12 and at week 24, we statistically tested the change from baseline between the groups with KRAS wild type (WT) and KRAS mutation (MUT) using the t-test. RECIST criteria for tumor response were used. Results: 3 patients had progressive disease (PD), 26 stable disease (SD), 8 partial response (PR) and 0 complete response. A KRAS MUT was found in 17 tumors (46%): 2 in PD (66.7%), 15 in SD (57.7%) and none in PR patients (p<0.01; responders vs. non responders). At 12 weeks there was a mean decrease in tumor size of 23.1% (SE=7.38) in the KRAS WT and an increase of 2.6% (SE=4.13) in the KRAS MUT mCRC. At 24 weeks KRAS WT and MUT mCRC had a 45.8% (SE=8.61) and a 1.3% (SE=6.67) mean decrease respectively (p= 0.0081 at 12 weeks; p=0.0015 at 24 weeks). The mean tumor size of the KRAS WT did not decrease further after 24 weeks. In the subgroup of SD tumor size regression was observed but only in WT patients. Mean time to progression was 32 (range 12–96) and 30 weeks (range 12–84) for KRAS WT (SD + PR) and MUT respectively. Conclusion: We confirmed KRAS MUT precludes objective response to CTX in mCRC. In addition we found tumor size regression in SD patients being restricted to WT patients. We observed rapid onset of these differences suggesting an important role of KRAS MUT status in early tumor shrinkage. However the onset of progression was not different according to KRAS MUT status. [Table: see text]

Download Full-text

EXPRESSÃO DAS PROTEÍNAS MUTANTES DO KRAS NO ADENOCARCINOMA COLORRETAL – REVISÃO BIBLIOGRAFICA

Revista de Patologia do Tocantins ◽

10.20873/uft.2446-6492.2019v6n1p50 ◽

2019 ◽

Vol 6 (1) ◽

pp. 50-53

Author(s):

Virgílio Ribeiro Guedes ◽

Natália Ferreira Bueno ◽

Victor Vargas de Oliveira ◽

Maria Cristina da Silva Pranchevicius

Keyword(s):

Colorectal Cancer ◽

Critical Role ◽

Google Scholar ◽

Ras Oncogene ◽

Kras Gene ◽

Gastrointestinal Malignancies ◽

Exon 2 ◽

First Line Therapy ◽

Keywords Colorectal Cancer ◽

The Right

Introdução: Os tumores colorretais foram o terceiro tipo de câncer mais diagnosticado em 2018. Na tentativa de aumentar a sobrevida de pacientes com metástases, o teste KRAS é relevante para a escolha da terapia mais apropriada para o carcinoma colorretal (CCR). O gene KRAS (Kirsten Ras Oncogene) acompanhado dos genes BRAF e NRAS é responsável por codificar as proteínas RAS da importante via de sinalização celular RAS/RAF/MEK/ERK. A presença de KRAS mutante no CCR é o principal biomarcador tecidual que indica a resistência do tumor à terapia de primeira linha com anticorpos monoclonais inibidores do EGFR (Cetuximabe e Panitumumabe). Metodologia: Foi realizado um levantamento bibliográfico na base eletrônica Google Scholar utilizando os descritores: “colorectal cancer” and “KRAS gene”. Resultados: A conversão do aminoácido glicina (G) para ácido aspártico (D) no códon 12, também chamada de KRAS G12D, é a mutação mais frequente do KRAS nas neoplasias malignas gastrointestinais. Cerca de 40% dos CCRs têm a mutação no gene KRAS nos códons 12 e 13 do éxon 2. Houve predomínio (57,4%) das mutações no sexo masculino, e todas as amostras de cólon esquerdo, 66% das de cólon direito e 51,8% das de reto apresentaram mutações no KRAS. A sinalização de células com KRAS mutante determina um papel crítico no rompimento inicial da submucosa e, por isso é essencial para a progressão da invasão e metástase do CCR. A eficácia de anti-EGFR é limitada em pacientes que possuem mutação KRAS, entretanto 20% dos pacientes com KRAS selvagem se beneficiam diante da terapia. Atualmente não há droga ou vacina que consiga focalizar efetivamente a proteína KRAS G12D em humanos. Conclusão: Pode-se inferir que o CCR é um câncer de prognostico ainda reservado. A decisão terapêutica apropriada depende do conhecimento do status mutacional do KRAS e as mutações no éxon 2 são claramente preditivas às terapias com anticorpos monoclonais inibidores do EGFR. Palavras-chave: Carcinoma colorretal; gene KRAS; mutação. ABSTRACT Introduction: Colorectal tumors were the third most diagnosed type of cancer in 2018. Trying to improve the overall survival of patients with metastasis, the KRAS test is relevant for choosing a mora appropriate therapy for the colorectal carcinoma (CRC). The KRAS gene (Kirsten Ras Oncogene) along with BRAF and NRAS genes is responsible for encoding RAS proteins from the important RAS / RAF / MEK / ERK cell signaling pathway. The presence of mutant KRAS in the CCR is the major tissue biomarker indicating the patient's resistance to first-line therapy with the monoclonal vaccine EGFR inhibitors (Cetuximabe and Panitumumabe). Methodology: A bibliographic survey was carried out in the database of Google Scholar using the descriptors: "colorectal cancer" and "KRAS gene". Results: The conversion of the amino acid glycine (G) to aspartic acid (D) at codon 12, also called KRAS G12D, is a more frequent mutation of KRAS in gastrointestinal malignancies. About 40% of the RCCs have a mutation in the KRAS gene at codons 12 and 13 of exon 2. There was a predominance (57.4%) of the mutations in the male sex, and all samples from the left colon, 66% of the right colon and 51.8% of the mutational changes in KRAS. Marking of cells with mutant KRAS determines a non-initial critical role of the submucosa and is therefore essential for progression of CCR invasion and metastasis. Anti-EGFR is limited to patients who have KRAS mutation, in addition, 20% of wild-type KRAS patients benefit from the therapy. There is currently no drug or vaccine that can concentrate on a KRAS G12D protein in humans. Conclusion: It can be inferred that the CRC still has a reserved prognosis. The multitude of KRAS and mutations in exon 2 are clearly prescribed in therapies with EGFR inhibitory monoclonal antibodies. Keywords: Colorectal cancer; KRAS gene; mutation.

Download Full-text

Impact of KRAS mutational status on clinical outcomes in patients receiving capecitabine based chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.436 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 436-436

Author(s):

Nirit Yarom ◽

Gillian Gresham ◽

Nana Boame ◽

Derek J. Jonker

Keyword(s):

Clinical Outcomes ◽

Kras Mutation ◽

Hazard Ratio ◽

Prognostic Impact ◽

Kras Gene ◽

Kras Mutations ◽

Mutation Status ◽

Mutational Status ◽

Kras Mutation Status ◽

Line Chemotherapy

436 Background: Mutations affecting the KRAS gene are established predictive markers of outcome with anti–epithelial growth factor receptor antibodies in metastatic colorectal cancer (mCRC). The relevance of these markers for chemotherapy has not been established. This analysis was performed to assess the predictive impact of KRAS mutation status in patients receiving chemotherapy. Methods: KRAS mutational status was available for 223 patients treated for mCRC. Predictive analysis of mutational status by type of fluoropyrmidine the 1st-line regimen contained (either capecitabine [C] based chemotherapy or infusional 5Fluorouracil [I-5Fu]) for clinical outcomes: progression-free survival (PFS), time to chemotherapy resistance (TTCR) and overall survival (OS). Results: KRAS mutations were observed in 43.5% of the patients. 165 patients received I-5Fu, 44 patients received C. KRAS mutation status (wild type [WT] v mutated [MT]) had no prognostic impact for OS (hazard ratio [HR], 0.81; CI, 0.69 to 1.1 p=0.17) for PFS (hazard ratio [HR], 0.87; CI, 0.66 to 1.14 p=0.3) and TTCR (hazard ratio [HR], 0.85; CI, 0.65to 1.12 p=0.26). C based 1st-line chemotherapy vs. I- 5FU based was predictive of PFS (hazard ratio [HR], 0.52; CI, 0.37 to 0.74 p=0.0003) and TTCR (hazard ratio [HR], 0.54; CI, 0.38 to 0.75p=0.0005) and not of OS (hazard ratio [HR], 0.74; CI, 0.52 to 1.1 p=0.1). KRAS mutational status had predictive impact in patients receiving C based 1st-line chemotherapy on OS (hazard ratio [HR], 0.47; CI, 0.23 to 0.948 p<0.0001) TTCR (hazard ratio [HR], 0.49; CI, 0.25 to 0.97 p=0.0398) and was not predictive of PFS (hazard ratio [HR], 0.78; CI, 0.4 to 1.53 p=0.47) Conclusions: KRAS gene mutation status was predicitve for OS and for TTCR in patients who received C based 1st-line chemotherapy.

Download Full-text