Frequency of Ras Mutations (Kras, Nras, Hras) in Human Solid Cancer

RAS oncogene affects numerous cellular functions including growth, proliferation, apoptosis, migration, division and differentiation of the cells. It has 3 known isoforms as HarveyRAS (HRAS), Kirsten RAS (KRAS) and NeuroblastomaRAS (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%.

[1]  Nikhil Wagle,et al.  Oncogenic mutations in cervical cancer , 2013, Cancer.

[2]  M. Inoue,et al.  K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary. , 1991, The American journal of pathology.

[3]  Y. Liu,et al.  Analysis of K-ras and p53 mutations in mesotheliomas from humans and rats exposed to asbestos. , 2000, Mutation research.

[4]  H. Morreau,et al.  Mutational analyses of epidermal growth factor receptor and downstream pathways in adrenocortical carcinoma. , 2013, European journal of endocrinology.

[5]  N. Dalay,et al.  Ras oncogene mutations in urine sediments of patients with bladder cancer. , 2003, Journal of biochemistry and molecular biology.

[6]  Wei Zhao,et al.  Mutations of PIK3CA in gastric adenocarcinoma , 2005, BMC Cancer.

[7]  R. Lothe,et al.  K-ras oncogene codon 12 point mutations in testicular cancer. , 1993, Environmental health perspectives.

[8]  J. Rey,et al.  Prognostic and Predictive Significance of MYC and KRAS Alterations in Breast Cancer from Women Treated with Neoadjuvant Chemotherapy , 2013, PloS one.

[9]  Supriya Patel,et al.  Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer , 2012, International journal of molecular sciences.

[10]  Suk Woo Nam,et al.  BRAF and KRAS mutations in stomach cancer , 2003, Oncogene.

[11]  George Vlachos,et al.  Consistent absence of BRAF mutations in cervical and endometrial cancer despite KRAS mutation status. , 2006, Gynecologic oncology.

[12]  R. Motzer,et al.  Infrequent ras oncogene point mutations in renal cell carcinoma. , 1990, The Journal of urology.

[13]  Jeongseon Kim,et al.  Gastric Cancer Epidemiology in Korea , 2011, Journal of gastric cancer.

[14]  G. Zhu,et al.  KRAS and BRAF mutations in prostate carcinomas of Chinese patients. , 2010, Cancer genetics and cytogenetics.

[15]  D. Saranath,et al.  Molecular lesions in human oral cancer: the Indian scene. , 1993, European journal of cancer. Part B, Oral oncology.

[16]  S. Shah,et al.  Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles , 2014, Modern Pathology.

[17]  Takashi Nakamura,et al.  Absence of oncogenic mutations of RAS family genes in soft tissue sarcomas of 100 Japanese patients. , 2010, Anticancer research.

[18]  D. Ogreid,et al.  Low-frequency mutation of Ha-ras and Ki-ras oncogenes in transitional cell carcinoma of the bladder. , 1998, Anticancer research.

[19]  D. Spandidos,et al.  Low incidence of H-, K- and N-ras oncogene mutations in cytological specimens of laryngeal tumours. , 1999, Oral oncology.

[20]  J. George,et al.  Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver , 2014, Clinical Cancer Research.

[21]  N. Omidifar,et al.  K-ras Mutation in Colorectal Cancer, A Report from Southern Iran , 2015, Iranian journal of medical sciences.

[22]  D. Sidransky,et al.  Inverse correlation between RASSF1A hypermethylation, KRAS and BRAF mutations in cervical adenocarcinoma. , 2007, Gynecologic oncology.

[23]  A. Iafrate,et al.  Targetable Signaling Pathway Mutations Are Associated with Malignant Phenotype in IDH-Mutant Gliomas , 2014, Clinical Cancer Research.

[24]  W. Lam,et al.  PIK3CA mutations and copy number gains in human lung cancers. , 2008, Cancer research.

[25]  S. Nasim,et al.  K-ras point mutations in endometrial carcinoma: effect on outcome is dependent on age of patient. , 1996, Gynecologic oncology.

[26]  G. Mills,et al.  Mutation Profiling in Cholangiocarcinoma: Prognostic and Therapeutic Implications , 2014, PloS one.

[27]  G. Fleuren,et al.  CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma. , 2014, Gynecologic oncology.

[28]  M. Brennan,et al.  The clinical approach to desmoplastic small round cell tumor. , 2000, Surgical oncology.

[29]  R W Ellis,et al.  Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[30]  A. Lopez‐Beltran,et al.  Unlike in clear cell renal cell carcinoma, KRAS is not mutated in multilocular cystic clear cell renal cell neoplasm of low potential , 2015, Virchows Archiv.

[31]  R. Caduff,et al.  Mutations of the Ki-ras oncogene in carcinoma of the endometrium. , 1995, American Journal of Pathology.

[32]  H. Tozkır,et al.  KRAS Mutation in Small Cell Lung Carcinoma and Extrapulmonary Small Cell Cancer. , 2016, Balkan medical journal.

[33]  Y. Hirai,et al.  Studies on ras oncogene activation in endometrial carcinoma , 1993, Gynecologic oncology.

[34]  T. Mairinger,et al.  The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study , 2013, BMJ Open.

[35]  M. Watson,et al.  RAS pathway activation and an oncogenic RAS mutation in sporadic pilocytic astrocytoma , 2005, Neurology.

[36]  A. Cossu,et al.  Prognostic impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a population-based study , 2016, Journal of Translational Medicine.

[37]  Bin Tean Teh,et al.  Exome sequencing of liver fluke–associated cholangiocarcinoma , 2012, Nature Genetics.

[38]  C. Challen,et al.  Infrequent point mutations in codons 12 and 61 of ras oncogenes in human hepatocellular carcinomas. , 1992, Journal of hepatology.

[39]  B. Przybojewska,et al.  H-RAS, K-RAS, and N-RAS gene activation in human bladder cancers. , 2000, Cancer genetics and cytogenetics.

[40]  S. Ouerhani,et al.  The prevalence and prognostic significance of KRAS mutation in bladder cancer, chronic myeloid leukemia and colorectal cancer , 2013, Molecular Biology Reports.

[41]  Larissa V Furtado,et al.  Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer , 2011, Genes, chromosomes & cancer.

[42]  D. Spandidos,et al.  Down-regulation of K-ras and H-ras in human brain gliomas. , 2009, European journal of cancer.

[43]  A. Ziaee,et al.  Mutations of RAS gene family in specimens of bladder cancer. , 2008, Urology journal.

[44]  Shuji Ogino,et al.  NRAS Mutations Are Rare in Colorectal Cancer , 2010, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

[45]  O. Abboud,et al.  Prevalence of K-RAS Codons 12 and 13 Mutations in Locally Advanced Head and Neck Squamous Cell Carcinoma and Impact on Clinical Outcomes , 2013, International journal of otolaryngology.

[46]  Jie Gao,et al.  Molecular spectrum of KRAS, NRAS, BRAF and PIK3CA mutations in Chinese colorectal cancer patients: analysis of 1,110 cases , 2015, Scientific Reports.

[47]  E. Alba,et al.  Lack of evidence for KRAS oncogenic mutations in triple-negative breast cancer , 2010, BMC Cancer.

[48]  J. Lundeberg,et al.  NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing , 2006, Melanoma research.

[49]  J. Shao,et al.  Oncotargets and Therapy Dovepress Oncogene Mutational Profile in Nasopharyngeal Carcinoma , 2022 .

[50]  M. Ligtenberg,et al.  EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma , 2012, Cellular Oncology.

[51]  M. Ladanyi,et al.  Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma , 2008, Clinical Cancer Research.

[52]  G. Reifenberger,et al.  Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas , 2004, Acta Neuropathologica.

[53]  A. Rademaker,et al.  Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[54]  S. Fesik,et al.  Drugging the undruggable RAS: Mission Possible? , 2014, Nature Reviews Drug Discovery.

[55]  Li-E. Wang,et al.  Clinical Correlates of NRAS and BRAF Mutations in Primary Human Melanoma , 2010, Clinical Cancer Research.

[56]  D. Spandidos,et al.  Mutational activation of k-ras oncogene in human breast-tumors. , 1994, International journal of oncology.

[57]  Wentao Yang,et al.  Comprehensive analysis of targetable oncogenic mutations in chinese cervical cancers , 2014, Oncotarget.

[58]  Carlota Costa,et al.  KRAS mutations in lung cancer. , 2013, Clinical lung cancer.

[59]  A. Flanagan,et al.  In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low‐grade serous tumours , 2004, The Journal of pathology.

[60]  M. Ladanyi,et al.  Characteristics of Lung Cancers Harboring NRAS Mutations , 2013, Clinical Cancer Research.

[61]  J. Yoo,et al.  H-ras and K-ras gene mutations in primary human soft tissue sarcoma: concomitant mutations of the ras genes. , 1999, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[62]  F. Sommerer,et al.  Mutations of BRAF and RAS are rare events in germ cell tumours , 2005, International journal of cancer.

[63]  Association between specific KRAS mutations and the clinicopathological characteristics of colorectal tumors. , 2015, Molecular and clinical oncology.

[64]  J. Bos,et al.  The ras gene family and human carcinogenesis. , 1988, Mutation research.

[65]  D. Spandidos,et al.  H-ras oncogene mutations in the urine of patients with bladder-tumors - description of a noninvasive method for the detection of neoplasia. , 1992, International journal of oncology.

[66]  B. Etschmann,et al.  Lack of KRAS and BRAF mutation in renal cell carcinoma. , 2009, European urology.

[67]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. , 2012, Neuro-oncology.

[68]  M. Barbacid,et al.  RAS oncogenes: the first 30 years , 2003, Nature Reviews Cancer.

[69]  C. Weiller,et al.  Further evidence for a somatic KRAS mutation in a pilocytic astrocytoma. , 2007, Neuropediatrics.

[70]  T. Nakajima,et al.  Molecular profiling of small cell lung cancer in a Japanese cohort. , 2014, Lung cancer.

[71]  M. Miwa,et al.  Mutation of K-ras protooncogene is associated with histological subtypes in human mucinous ovarian tumors. , 1994, Cancer research.

[72]  J. Downward Targeting RAS signalling pathways in cancer therapy , 2003, Nature Reviews Cancer.

[73]  A. Nagy,et al.  Investigation of c-myc and K-ras amplification in renal clear cell adenocarcinoma. , 1997, Cancer letters.

[74]  P. Stephens,et al.  Next-generation sequencing of adrenocortical carcinoma reveals new routes to targeted therapies , 2014, Journal of Clinical Pathology.

[75]  M. Inoue,et al.  K-ras activation in premalignant and malignant epithelial lesions of the human uterus. , 1991, Cancer research.

[76]  M. Kew,et al.  Analysis of ras gene mutations in hepatocellular carcinoma in southern African blacks. , 1995, Anticancer research.

[77]  Ken Kato,et al.  Clinicopathological features and prognostic roles of KRAS, BRAF, PIK3CA and NRAS mutations in advanced gastric cancer , 2014, BMC Research Notes.

[78]  O. Ozdemır,et al.  K-Ras mutation in transitional cell carcinoma of urinary bladder , 2004, International Urology and Nephrology.

[79]  G. Scambia,et al.  Mutational status of KRAS, NRAS, and BRAF in primary clear cell ovarian carcinoma , 2014, Virchows Archiv.

[80]  Kyung Chul Moon,et al.  BRAF and KRAS mutations in prostatic adenocarcinoma , 2006, International journal of cancer.

[81]  J. Uhm Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2009 .

[82]  D. Shibata,et al.  Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes , 1988, Cell.

[83]  A. Vortmeyer,et al.  Integrated genomic characterization of IDH1-mutant glioma malignant progression , 2015, Nature Genetics.

[84]  A. Berchuck,et al.  Molecular basis of endometrial cancer , 1995, Cancer.

[85]  T. Uchida,et al.  Infrequent involvement of mutations on neurofibromatosis type 1, H-ras, K-ras and N-ras in urothelial tumors. , 1995, Urologia internationalis.

[86]  J. Jeng,et al.  Mutations of Ki-ras oncogene codon 12 in betel quid chewing-related human oral squamous cell carcinoma in Taiwan. , 1994, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[87]  M. Stratton,et al.  COSMIC 2005 , 2006, British Journal of Cancer.