Faculty Opinions recommendation of MLH1-deficient Colorectal Carcinoma With Wild-type BRAF and MLH1 Promoter Hypermethylation Harbor KRAS Mutations and Arise From Conventional Adenomas.

Pancreatitis, an inflammation of the pancreas, appears to be a main driver of pancreatic cancer when combined with Kras mutations. In this context, the exact redox mechanisms are not clearly elucidated. Herein, we treated mice expressing a KrasG12D mutation in pancreatic acinar cells with cerulein to induce acute pancreatitis. In the presence of KrasG12D, pancreatitis triggered significantly greater redox unbalance and oxidative damages compared to control mice expressing wild-type Kras alleles. Further analyses identified the disruption in glutathione metabolism as the main redox event occurring during pancreatitis. Compared to the wild-type background, KrasG12D-bearing mice showed a greater responsiveness to treatment with a thiol-containing compound, N-acetylcysteine (NAC). Notably, NAC treatment increased the pancreatic glutathione pool, reduced systemic markers related to pancreatic and liver damages, limited the extent of pancreatic edema and fibrosis as well as reduced systemic and pancreatic oxidative damages. The protective effects of NAC were, at least, partly due to a decrease in the production of tumor necrosis factor-α (TNF-α) by acinar cells, which was concomitant with the inhibition of NF-κB(p65) nuclear translocation. Our data provide a rationale to use thiol-containing compounds as an adjuvant therapy to alleviate the severity of inflammation during pancreatitis and pancreatic tumorigenesis.

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Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma

Oncotarget ◽

10.18632/oncotarget.9682 ◽

2016 ◽

Vol 7 (32) ◽

pp. 50875-50882 ◽

Cited By ~ 12

Author(s):

Breanna M. Javier ◽

Rona Yaeger ◽

Lu Wang ◽

Francisco Sanchez-Vega ◽

Ahmet Zehir ◽

...

Keyword(s):

Colorectal Carcinoma ◽

Kras Mutation ◽

Wild Type

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Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer

World Journal of Gastroenterology ◽

10.3748/wjg.v13.i12.1767 ◽

2007 ◽

Vol 13 (12) ◽

pp. 1867 ◽

Cited By ~ 24

Author(s):

Yaron Niv

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Promoter Hypermethylation ◽

Mlh1 Promoter

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CMET-18. IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES

Neuro-Oncology ◽

10.1093/neuonc/noz175.219 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi55-vi55

Author(s):

Adam Lauko ◽

Assad Ali ◽

Soumya Sagar ◽

Addison Barnett ◽

Hong Li ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastasis ◽

Brain Metastases ◽

Checkpoint Inhibitors ◽

Care Center ◽

Tertiary Care ◽

Wild Type ◽

Chi Square ◽

Kras Mutations ◽

Mutational Status

Abstract BACKGROUND Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.

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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.

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

Diagnostics ◽

10.3390/diagnostics10110872 ◽

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.

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