scholarly journals Prognostic Value of KRAS Gene Mutation on Survival of Patients with Peritoneal Metastases of Colorectal Adenocarcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Manuel Díez-Alonso ◽  
Fernando Mendoza-Moreno ◽  
Remedios Gómez-Sanz ◽  
Belén Matías-García ◽  
Enrique Ovejero-Merino ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Prognostic Value ◽  
Cox Regression ◽  
Peritoneal Cancer Index ◽  
Strong Association ◽  
Peritoneal Metastases ◽  
Wild Type ◽  
Kras Gene ◽  
Term Survival ◽  
Mutational Status

Objective. The main objective of the study was to determine the effect of the presence of mutation in the KRAS gene on the survival in patients with colorectal cancer (CRC) and peritoneal metastases (PM). Materials and Methods. A retrospective cohort study was performed. Patients diagnosed with CRC with synchronous or metachronous PM between January 2006 and December 2019 were included. Data on the histopathological, clinical, and treatment factors were collected. The effect of each variable on survival was evaluated by Cox regression. Results. A total of 149 patients were included (64 women (43%) and 85 men (57%); mean age, 63 years). The long-term survival rate at 36 months was 24% (median, 21 months). KRAS mutation was detected in 75 patients (50.3%). Kaplan–Meier analysis estimated that likelihood of survival was higher in patients with wild-type KRAS tumours (35%) than in mutated-type KRAS (14%) (median: 28 vs. 15, respectively) ( P = 0.001 ). Within the categories into which the peritoneal cancer index (PCI) was classified, survival at 36 months depended on the KRAS status. Survival in wild-type KRAS tumours with PCI 1–10 was 71% and with PCI 11–20 was 26%, while in mutant-type KRAS tumours, survival was 41% and 4%, respectively ( P = 0.025 ). In the multiple regression analysis, the KRAS mutation was revealed to have an independent prognostic value (HR: 2.144; 95% CI: 1.342–3.424). Conclusion. The mutational status of the KRAS gene has demonstrated a strong association with survival and prognostic utility in patients with CRC with PM.

Age-dependent prognostic value of KRAS mutation in metastatic colon cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16085-e16085
Author(s):  
Muhammet Ozer ◽  
Suleyman Yasin Goksu ◽  
Nina Niu Sanford ◽  
Todd Anthony Aguilera ◽  
Radhika Kainthla ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Kras Mutation ◽  
Prognostic Value ◽  
Cox Regression ◽  
Categorical Variables ◽  
Metastatic Colon Cancer ◽  
Tumor Characteristics ◽  
Wild Type ◽  
Kras Status ◽  
Age Dependent

e16085 Background: KRAS mutation is associated with poor prognosis in metastatic colon cancer (mCC). However, the age-dependent prognostic value of KRAS status is unknown. We aimed to confirm if the prognostic impact of KRAS is dependent on the age of diagnosis in mCC. Methods: We identified adult patients with mCC diagnosed between 2004 and 2016 using the NCDB. We compared patients with KRAS mutation and KRAS wild type, stratified according to age group < 50, 50-70, and ≥70. Categorical variables were compared using the chi-square test. We performed the Kaplan-Meier and Cox regression methods for survival analyses. We adjusted for patient and tumor characteristics (included KRAS status, MSI, 18q loss of heterozygosity, side of the primary tumor). Results: A Total of 19,875 patients had KRAS status reported; 43% had KRAS mutation, and 57% were KRAS wild type. Patients with KRAS mutation were more likely to be female, black, have elevated CEA, and have right-sided tumors (all p < .001). In the overall population, patients with KRAS mutation had significantly worse OS compared to patients with KRAS wild type (20 vs. 22 months, p < .001), and this difference was maintained after multivariable Cox regression analysis ( p < .001) (Table). Young patients ( < 50 years) with KRAS mutation had a worse prognosis than those with KRAS wild type in the tumor (23 vs. 29 months, p < .001). KRAS status did not maintain its prognostic value among older age (≥70 years) patients (14 vs. 14 months, p = NS). Conclusions: In this analysis of a national cancer registry, we confirmed that KRAS mutation was an independent poor prognostic factor for mCC. This effect persisted after adjusting for patient and tumor characteristics, including sidedness and MSI status. However, we identified that this prognostic value of KRAS mutation is significant in young mCC patients < 50 years, as compared to older patients. [Table: see text]

Co-existance of KRAS and LKB1 mutation as predictor of resistance to Erlotinib: Customized next-generation sequencing (NGS) of TAILOR trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20631-e20631
Author(s):  
Eliana Rulli ◽  
Mara Serena Serafini ◽  
Mirko Marabese ◽  
Elisa Caiola ◽  
Gabriella Sozzi ◽  
...  
Keyword(s):  
Predictive Value ◽  
Kras Mutation ◽  
Cox Regression ◽  
Cell Metabolism ◽  
Future Research ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Mutational Status ◽  
Key Factor ◽  
Worse Prognosis

e20631 Background: The prognostic and predictive value of KRAS mutation in advanced NSCLC is still debatable. In TAILOR (NCT00637910) trial EGFR wild-type patients were randomized to receive 2nd line erlotinib versus docetaxel, and no interaction was detected according to KRAS mutational status. Recent evidences indicate that the concurrent mutation of KRAS and LKB1 (key factor for cell metabolism) may be associated with worse prognosis. Methods: Availableformalin-fixed embeddedtissue samples with annotated clinical data from TAILOR were gathered. Customized deep sequencing (Ion proton Technology) of 111 genes most frequently associated with cancer, was performed; 5% of frequency was used to identify mutations. Association between genes and clinical features was performed with non-parametric tests; Cox regression analysis was used to assess the prognostic and predictive value of LKB1. Results: 123 out of 222 (55%) randomized patients had available tissue and were successfully sequenced. 42/123 (34%) patients had a KRAS mutation. KRAS and LKB1 mutations were found in 11/42 (26%) KRAS patients, while only 6 patients had a LKB1 mutation without KRAS. The presence of a concurrent KRAS-LKB1 mutation did not adversely influence progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS 1.08, 95% confidence interval (CI) 0.57-2.05, P = 0.81; OS 1.09, 95% CI 0.56-2.14, P = 0.78]. Patients receiving docetaxel experienced longer survival regardless of the KRAS-LKB1 mutational status (mutated KRAS-LKB1 HR 0.42, 95% CI 0.08-2.29; wild-type KRAS-LKB1 HR 1.16, 95% CI 0.72-1.87, P = 0.55; interaction P = 0.10). Conclusions: Although the significant attrition and the limited number, these data generate the hypothesis that the concurrent mutation of KRAS and LKB1 may potentially be associated with resistance to erlotinib. Overall, the coexistence of mutation in KRAS and LKB1 is not associated with worse prognosis in NSCLC. For these patients refractory to EGFR targeting, metabolic strategies represent a future research opportunity.

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

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1514 ◽  
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.

scholarly journals Allele-Specific PCR for KRAS Mutation Detection Using Phosphoryl Guanidine Modified Primers

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 872
Author(s):  
Alexey S. Chubarov ◽  
Igor P. Oscorbin ◽  
Maxim L. Filipenko ◽  
Alexander A. Lomzov ◽  
Dmitrii V. Pyshnyi
Keyword(s):  
Kras Mutation ◽  
Mutation Detection ◽  
Synergetic Effect ◽  
Model Systems ◽  
Wild Type ◽  
Kras Mutations ◽  
Specific Pcr ◽  
Mutational Status ◽  
Allele Specific ◽  
Pcr Method

Establishing the Kirsten rat sarcoma (KRAS) mutational status is essential in terms of managing patients with various types of cancer. Allele-specific real-time polymerase chain reaction (AS-PCR) is a widely used method for somatic mutations detection. To improve the limited sensitivity and specificity, several blocking methods have been introduced in AS-PCR to block the amplification of wild-type templates. Herein, we used a novel modified oligonucleotide with internucleotide phosphates reshaped 1,3-dimethyl-2-imino-imidazolidine moieties (phosphoryl guanidine (PG) groups) as primers and blockers in the AS-PCR method. Four common KRAS mutations were chosen as a model to demonstrate the advantages of the PG primers and blockers utilizing a customized PCR protocol. The methods were evaluated on plasmid model systems providing a KRAS mutation detection limit of 20 copies of mutant DNA in a proportion as low as 0.1% of the total DNA, with excellent specificity. PG-modification can serve as the universal additional mismatch-like disturbance to increase the discrimination between wild-type and mutated DNA. Moreover, PG can serve to increase primer specificity by a synergetic effect with additional mismatch and would greatly facilitate medical research.

Preliminary report of the mutation status of KRAS and BRAF-V600E in an Argentinean population of primary colorectal tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22183-e22183
Author(s):  
F. Perazzo ◽  
V. Denninghoff ◽  
G. Pasccon ◽  
M. G. Pallotta ◽  
M. Tatangelo ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Preliminary Report ◽  
Collaborative Study ◽  
Point Mutations ◽  
Pcr Amplification ◽  
Braf V600e ◽  
Wild Type ◽  
Primary Tumor Site ◽  
Mutational Status ◽  
History Of

e22183 Background: Several studies have suggested that KRAS somatic mutations predict resistance to Cetuximab treatment in colorectal cancers. The aim of this report is to present the mutational status of KRAS, BRAF and epidemiological data of an Argentinean population of CR tumors which may have future clinical practice implications. Methods: Patients were prospectively selected from the databases of 8 Argentinean public and private hospitals with colorectal cancer between January and December 2008. We analyzed the presence of KRAS point mutations in codons 12 and 13, and the BRAF-V600E from formalin fixed sections with Polymerase Chain Reaction (PCR) amplification-sequencing. Results: A total of 146 patients, 41.8% (61) F and 57.2% (85) M, with a median age of 58.1 years (range, 17–88), 45.2% (66) were current smokers, 50% (73) never smoke. 41.4% (60) have family history of cancer and 9.6% (14) have personal history of a previous tumor. 63.2% were European Caucasian, 30.3% American Caucasian and 0.7% of Asian origin. The media BMI was 25.9 (range, 16- 47). The primary tumor site was 21.9% (32) right colon, 5.5% (8) transverse colon, 45.2% (66) left colon and 27.4%(40) rectal cancer. Adenocarcinoma was the unique histotype and mucinous differentiation was observed in 14.7% (21). The Pathological Stage at diagnosis was Stage I 3.42% (5), II 24% (35), III 33.6% (49) and IV 39% (57). 60.3% (88) where found to be wild type, while the other 39.7% (58) showed the KRAS mutation in the following amino acids: GLY12ALA 5.2% (3), GLY12ASP 25.9% (15), GLY12CYS 3.4% (2), GLY12SER 1.7% (1), GLY12VAL 62.1 % (36), GLY13ARG 1.7% (1). We analyzed in 49 patients the mutational status of BRAF-V600E, only 2 patients showed the presence of both mutations, 23 presented BRAF and KRAS wild type, 20 had a KRAS mutation while the BRAF was wild type, only 4 patients reveled a mutation of BRAF in the presence of a KRAS wild type. Conclusions: This is the first Argentinean collaborative study of the mutational status of KRAS and BRAF. Our preliminary report based in 146 patients, revealed similar mutational KRAS results in codon 12 and 13 than the reports of Europe. This is probably due to the ethnic origin of Argentinean population. No significant financial relationships to disclose.

Expression level of NRP1 and SMAD2 in correlation to mutational status of RAS (BRAF) in pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15784-e15784
Author(s):  
Libor Stanek ◽  
Petra Tesarova ◽  
Robert Gurlich
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Gene Mutation ◽  
Expression Level ◽  
Wild Type ◽  
Braf Gene ◽  
Kras Gene ◽  
Mutation Status ◽  
Mutational Status ◽  
Neuropilin 1

e15784 Background: Pancreatic cancer is the second leading cause of death in tumor diseases worldwide. Neuropilin-1 (NRP1) is overexpressed in many tumors including the pancreatic cancer. The main goal is to reveal the role of NRP1 in the process of tumorigenesis. The expression of NRP1 and the presence of KRAS point mutation lead to the cell survival by lowering the SMAD2 phosphorylation. On the other hand, the NRP1 inactivation and the wild-type KRAS in tumor cells lead to the tumor growth inhibition. Our aim is to prove correlation between NRP1 level, SMAD2 and the mutational status of KRAS, NRAS in prognosis of patients with pancreatic cancer. Methods: Retrospective study is based on analysis of 50 FFPE bioptical samples (40 resections, 8 punctures, 2 thin-needle biopsies); histology verified all as adenocarcinomas. The expression level of NRP1 and SMAD2 is measured by Imunohistochemistry by mice monoclonal antibodies Anti-Neuropilin 1 and Anti-SMAD2 (Abcan) on the device BenchMark ULTRA (Ventana Medical Systems), Roche. DNA isolation is executed by QIAamp DNA Mini Kit. We used Codon Specific Mutation Detection Kit (Diatech pharmacogenetics) for detection of somatic point mutations in codons 12, 13, 61 and 146 of KRAS and NRAS genes. BRAF mutational status was revealed by direct sequencing on ABI Prism 3130. We monitor the level of expression of NRP1 and SMAD2 and correlate it to the mutational status of RAS and BRAF, and disease prognosis. Results: NRP1 expression was detected in 24 out of 50 cases, SMAD2 expression was detected in 13 of 50 cases, other cases without expression. KRAS gene mutation was detected in 8 cases out of 60, other cases of WT. Mutation in the NRAS gene was detected in 3 of 50 cases. BRAF gene mutation was detected in 1 case out of 50, other WT. NRP1 expression correlated with KRAS gene mutation status in 9 cases and a strong correlation (p = < 0.001) was recorded. One case of mutation in the BRAF gene correlated with KRAS mutation status and NRP1 expression. Due to the small number of samples tested, without statistical significance. Inactivation of NRP1 was detected in 15 cases and was confirmed by the WT status of the KRAS gene. Conclusions: Was demonstrated that causal relationship exists between inactive NRP1 and wild-type KRAS, and that these should cause decrease of the rate of tumor growth. These characteristics, which are achievable simultaneously during the histological verification, may serve as a potential prognostic marker for subsequent decision of how radical surgical resection should be.

Mutation of DNA damage repair genes confers an immune-privileged tumor microenvironment in colorectal cancer with a prognostic value.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4080-4080
Author(s):  
Dandan Liang ◽  
Huan Chen ◽  
Ying Yang ◽  
Guanxiong Zhang ◽  
Jiao Zhang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Immune Checkpoint ◽  
Prognostic Value ◽  
Dna Damage Repair ◽  
Cancer Center ◽  
Wild Type ◽  
Cancer Immunity ◽  
Mutational Status ◽  
Damage Repair ◽  
Significant Difference

4080 Background: Microsatellite instability high (MSI-H)/mismatch-repair-deficient (dMMR) has been proved as a validated biomarker in solid tumors receiving immune checkpoint inhibitors (ICIs). Recently, mutational status of the DNA damage repair (DDR) genes has been linked to anti-tumor immune response in bladder cancer. Therefore, it would be of great interest to unravel the implications of DDR in shaping the immune responsiveness in CRC. Methods: The genomic correlates were examined in a publicly available cohort from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To explore the associations between DDR mutation and immune features, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was analyzed. Further, we determined DDR mutation and MSI status in a Chinese CRC cohort via a 543-gene panel sequencing. Results: First, we observed that DDR pathway was commonly mutated (21.79%) in the multi-cancer MSK ICI cohort, with the highest frequency of 36.36% in CRCs. Second, survival analysis revealed that the median overall survival (mOS) in patients with DDR mutations was significantly longer than that in the DDR wild-type subgroup, in both pan-cancer (P = 0.0008; mOS 31 vs 16 months) and CRC patients (P = 0.016; mOS 34 vs 13 months) in the MSK ICI cohort. However, in the TCGA COADREAD dataset, there was no significant difference in OS or progression free survival (PFS) between DDR mutant and DDR wild-type subgroups. These observation indicated a specific prognostic value for DDR mutation in patients with ICI treatment while not conventional treatment. Third, in the TCGA COADREAD dataset, DDR mutations were associated with increased TMB, enrichment of immune cell infiltration and immune checkpoint molecule expression, suggesting an improvement of various steps of the cancer immunity cycles in DDR mutant CRCs. Lastly, we investigated the DDR mutational pattern, and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation account for 5.7% and 13.4% respectively, suggesting that DDR may identify a higher proportion of potential responders than MSI-H. Conclusions: Our data suggest that DDR mutation is a potential prognostic biomarker for ICI-treated CRCs. Functional analysis in TCGA dataset revealed that DDR mutation might be an indication of enhanced cancer immunity. The higher incidence of DDR mutation in Chinese CRCs emphasized the future utility of panel-based DDR evaluation in guiding ICI treatment.

KRAS mutation, cancer recurrence, and patient survival in stage III colon cancer: Findings from CALGB 89803

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4037-4037
Author(s):  
C. Fuchs ◽  
S. Ogino ◽  
J. A. Meyerhardt ◽  
N. Irahara ◽  
D. Niedzwiecki ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Kras Mutation ◽  
Patient Survival ◽  
Stage Iii ◽  
Wild Type ◽  
Stage Iii Colon Cancer ◽  
Mutational Status ◽  
Disease Free

4037 Purpose: KRAS mutation in stage IV colorectal cancer predicts resistance to anti-EGFR targeted treatment (cetuximab or panitumumab). However, whether the presence of KRAS mutation independently predicts the survival of colon cancer patients remains uncertain. Methods: We conducted a prospective observational study of 508 cases identified among 1264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) between April 1999 and May 2001 (CALGB 89803; Saltz et al. J Clin Oncol 2007). KRAS mutations were detected in 178 tumors (35%) by Pyrosequencing. Kaplan-Meier and Cox proportional hazard models were used to assess the significance of KRAS mutational status and adjusted for potential confounders including age, sex, tumor location, T stage, N stage, performance status, adjuvant chemotherapy arm and microsatellite instability (MSI) status. Results: When compared to patients with wild-type KRAS, those with a mutation in KRAS did not experience any difference in disease-free (DFS), recurrence-free (RFS), or overall survival (OS) (log-rank P>0.56 for DFS, RFS, and OS). Five-year DFS was 62% for KRAS-mutated and 63% for KRAS-wild-type patients. Five-year RFS was 64% for KRAS-mutated and 66% for KRAS- wild-type patients. Five-year OS was 74% for KRAS-mutated and 73% for KRAS-wild-type patients. The effect of KRAS mutation on patient survival did not differ according to clinical features, chemotherapy arm or MSI status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status. Conclusions: In this large clinical trial of chemotherapy in patients with stage III colon cancer, KRAS mutational status was not associated with any significant influence on disease-free or overall survival. No significant financial relationships to disclose.

Insulin Growth Factor 1 Receptor Expression Is Associated with NOTCH1 Mutation, Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3314-3314
Author(s):  
Francesco Maura ◽  
Laura Mosca ◽  
Fabris Sonia ◽  
Giovanna Cutrona ◽  
Serena Matis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Strong Association ◽  
Lymphocytic Leukemia ◽  
Wild Type ◽  
Insulin Growth Factor ◽  
Cd38 Expression ◽  
Mutational Status ◽  
Hematological Cancers ◽  
Trisomy 12 ◽  
Igf1r Expression

Abstract Insulin growth factor 1 receptor (IGF1R) is emerging as an important gene in many solid and hematological cancers and its over expression has been reported to be associated with aggressive disease and pharmacologic resistance. Specifically, the IGF1R-IGF1-2 interaction was recently described to be involved in the constitutive activation of many important cell signaling such as NOTCH1 and PI3K/Akt pathways that play a key role in many solid and hematological cancers. In this study we performed a clinical and biological investigations about the role of IGF1R expression in a large and representative prospective series of chronic lymphocytic leukemia (CLL) in Binet A clinical stage enrolled in observation O-CLL1 protocol (clinicaltrial.gov identifier NCT00917540). Total RNA extraction, preparation of DNA single-stranded sense target, and hybridization to gene expression profiling arrays were carried out according to manufacturer’s protocols in 217 CLL patients enrolled in the multicentre O-CLL1 protocol. Gene expression data has been deposited in the National Centre for Biotechnology Information’s Gene Expression Omnibus database http://www.ncbi.nlm.mih.gov/geo and are accessible through series accession number GSE51529. High IGF1R expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high ZAP-70 and CD38 expression (p<0.0001) and unfavorable cytogenetic deletion [i.e. del(11)(q23) and del(17)(p13)], particularly with del(11)(q23) (p=0.03). Cases with del(13)(q14) as single lesion were characterized by the lowest IGF1R gene levels. On the contrary, among the most common cytogenetic aberrations, trisomy 12 showed stronger IGF1R expression compared with the other patients (p<0.0001) and this association was independent from IGHV mutational status. Patients with stereotyped HCDR3 sequences showed a greater IGF1R expression compared to not stereotyped HCDR3 (p=0.001) even if this can be related to the high frequency of IGHV-UM among stereotyped HCDR patients. Interestingly, subset #4 patients, who are known to exhibit an indolent clinical course and distinct biological profile, were also characterized by lower IGF1R expression compared to other M-IGHV and UM-IGHV patients. NOTCH1 c.7541_7542delCT mutation was investigated by next generation sequencing Roche 454 technology in 199 (92%) patients (Lionetti et al, BJH 2014). Globally, median depth of coverage was 1510x, ranging from 605 to 2842. Mutant allele frequency estimated by NGS ranged from 0.02% to 75% of total reads per sample. The presence of NOTCH1 mutation was confirmed by ASO-PCR and Sanger sequencing in all patients with allele burden higher > 0.7% (31; 15.5%) and 7% (19; 9.5%) respectively. We considered as mutated only the 31 patients in whom the presence of the dinucleotide deletion was confirmed by ARMS-PCR. Patients carrying NOTCH1 mutation were characterized by a greater IGF1R expression compared with wild type cases (p=0.002). In addition high IGF1R expression was not significantly different comparing patients with low and high NOTCH1 mutation burden. In order to avoid the bias represented by the strong association between NOTCH1 and trisomy 12, we compared the IGF1R expression between NOTCH1 mutated and wild type cases excluding trisomy 12, and confirmed the previous association (p=0.004). IGF1R expression represented a strong clinical prognostic factor in our CLL cohort: by Kaplan-Maier analysis we observed a significant time to first treatment stratification in all CLLs, in all IGHV-UM and in all IGHV-M patients (p<0.0001). Furthermore, IGF1R retained its significance in multivariate analysis with most important clinical and molecular prognostic factors (CD38 expression, unfavorable FISH and IGHV mutational status). Overall, our study shows the importance of IGF1R expression in CLL and its strong association with specific clinical and biological features, confirming the interest for the study of this gene as a potential prognostic factor and its possible role as a therapeutic target in a specific group of CLL patients carrying trisomy 12 and NOTCH1 mutations. Disclosures No relevant conflicts of interest to declare.

scholarly journals KRAS gene mutation in patients with primary colorectal cancer

Acta Medica ◽  
2019 ◽  
Vol 50 (1) ◽  
pp. 20-25
Author(s):  
Minh Thuc Vu Thi ◽  
Van Thieu Le ◽  
Quang Huy Huynh ◽  
Minh Duc Nguyen
Keyword(s):  
Colorectal Cancer ◽  
Gene Mutation ◽  
Kras Mutation ◽  
Pcr Amplification ◽  
Colorectal Cancers ◽  
Kras Gene ◽  
Kras Mutations ◽  
Exon 2 ◽  
Mutational Status ◽  
Keywords 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.

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