Association between specific KRAS mutations and the clinicopathological characteristics of colorectal tumors

Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset. This analysis reveals insights into small-molecule mechanisms of action, and genomic features that associate with CCL response to small-molecule treatment. We are able to recapitulate known relationships between FDA-approved therapies and cancer dependencies and to uncover new relationships, including for KRAS-mutant cancers and neuroblastoma. To enable the cancer community to explore these data, and to generate novel hypotheses, we created an updated version of the Cancer Therapeutic Response Portal (CTRP v2).

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“…S8E; ref. 40). These preliminary data suggest that ACME analysis of profiling data may be useful in nominating compounds for combination testing.…”

Section: Resultsmentioning

confidence: 99%

Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset

et al. 2015

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“…KRAS mutation prevalence in cholangiocarcinoma ranged from 16% to 38%. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] …”

Section: Frequency Of Ras Mutation In Gastrointestinal Cancermentioning

confidence: 99%

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

Kodaz

2017

EJMO

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T he RAS oncogene affects numerous cellular functions, including growth, proliferation, apoptosis, migration, division, and differentiation of the cells. It has 3 known isoforms: Harvey-RAS (HRAS), Kirsten-RAS (KRAS), and neuroblastoma-RAS (NRAS). RAS has an intrinsic GTPase activity; it encodes proteins binding the guanine nucleotides. KRAS and HRAS were discovered in studies conducted on cancer-causing viruses. Retroviral oncogenes related to murine sarcoma virus genes (Kristen rat sarcoma virus and Harvey rat sarcoma virus) were discovered in 1982. These 2 oncogenes are similar to human KRAS. Approximately 30% of all human cancers have RAS gene involvement. Mutations in KRAS account for about 85% of all RAS mutations in human tumors, NRAS for about 11% to 15%, and HRAS for about 1%. Frequency of RAS mutation in intracranial tumorsGliomas constitute 80% of malignant brain tumors. RAS mutations are very rare in malignant gliomas; no RAS mutation was found in a study in which 30 glioblastoma multiforme (GBM) patients were evaluated. The frequency of NRAS mutation was 2.1% in another study, although KRAS and HRAS mutations were not detected. It was reported that RAS mutation frequency was 12% in a study of isocitrate-dehydrogenase 1-mutant malignant glioma. RAS genes were studied in 21 cases of glioblastoma multiforme, 4 cases of fibrillary astrocytoma, 4 cases of anaplastic astrocytoma, and 15 normal specimens. RAS mutation was de-RAS oncogene affects numerous cellular functions including growth, proliferation, apoptosis, migration, division and differentiation of the cells. It has 3 known isoforms as Harvey-RAS (HRAS), Kirsten -RAS (KRAS) and Neuroblastoma-RAS (NRAS). RAS has an intrinsic GTPase activity. It encodes proteins binding the guanine nucleotides. KRAS and HRAS were discovered in studies carried out on viruses leading to cancer. Retroviral oncogenes related to murine sarcoma virus genes (Kristen Rat Sarcoma Virus and Murine Sarcoma Virus) were discovered in 1982. These two oncogenes are similar to human KRAS. Approximately 30% of all human cancers have ras genes. Mutations in KRAS account for about 85% for all RAS mutations in human tumors, NRAS is about 11-15%, and HRAS is about 1%.

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“…Genetic, dietary and environmental factors play a role in the development of KRAS mutations. More than 80% of KRAS mutations are exon 2 mutations in NSCLC and colorectal cancers (19,23). In our study, 80% of KRAS mutations in SCLC were in exon 3.…”

Section: Discussionmentioning

confidence: 78%

“…In our study, 6 (16.2%) of 37 SCLC patients had KRAS mutations. There were ethnic and geographical differences in the KRAS mutation status of patients with colorectal cancer and NSCLC (19,23,24). Genetic, dietary and environmental factors play a role in the development of KRAS mutations.…”

Section: Discussionmentioning

confidence: 99%

KRAS Mutation in Small Cell Lung Carcinoma and Extrapulmonary Small Cell Cancer

et al. 2016

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Background: Lung cancer is one of the most lethal cancers. It is mainly classified into 2 groups: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Extrapulmonary small cell carcinomas (EPSCC) are very rare. The Ras oncogene controls most of the cellular functions in the cell. Overall, 21.6% of human cancers contain a Kirsten Ras (KRAS) mutation. SCLC and EPSCC have several similar features but their clinical course is different. Aims: We investigated the KRAS mutation status in SCLC and EPSCC. Study design: Mutation research. Methods: Thirty-seven SCLC and 15 EPSCC patients were included in the study. The pathological diagnoses were confirmed by a second pathologist. KRAS analysis was performed in our medical genetic department. DNA isolation was performed with primary tumor tissue using the QIAamp DNA FFPE Tissue kit (Qiagen; Hilden, Germany) in all patients. The therascreen KRAS Pyro Kit 24 V1 (Qiagen; Hilden, Germany) was used for KRAS analyses. Results: Thirty-four (91.9%) of the SCLC patients were male, while 11 (73.3%) of the EPSCC l patients were female. SCLC was more common in males, and EPSCC in females (p=0.001). A KRAS mutation was found in 6 (16.2%) if SCLC patients. The most common mutation was Q61R (CAA>CGA). Among the 15 EPSCC patients, 2 had a KRAS mutation (13.3%). When KRAS mutant and wild type patients were compared in the SCLC group, no difference was found for overall survival (p=0.6). Conclusion: In previous studies, the incidence of KRAS mutation in SCLC was 1-3%; however, it was 16.2% in our study. Therefore, there may be ethnic and geographical differences in the KRAS mutations of SCLC. As a result, KRAS mutation should not be excluded in SCLC.

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Association between specific KRAS mutations and the clinicopathological characteristics of colorectal tumors

Cited by 22 publications

References 21 publications

Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset

Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset

Frequency of RAS Mutations (KRAS, NRAS, HRAS) in Human Solid Cancer

KRAS Mutation in Small Cell Lung Carcinoma and Extrapulmonary Small Cell Cancer

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