RAS oncogenes: the first 30 years

Malumbres, Marcos; Barbacid, Mariano

doi:10.1038/nrc1097

Cited by 1,591 publications

(1,304 citation statements)

References 114 publications

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“…23 Mutations in KRAS are early events in tumorigenesis, and commonly occur in tumors showing mucinous differentiation in various organs, including the pancreas (90%), colon (50%), thyroid (50%), and lung (30%). 24 Mutated KRAS is more frequent in ovarian mucinous borderline tumors or carcinomas (75%) than in serous carcinomas (20%) or other non-mucinous ovarian tumors (14%).…”

Section: Discussionmentioning

confidence: 99%

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

et al. 2012

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Mucinous adenocarcinoma is an uncommon type of endometrial adenocarcinoma for which precursor lesions have yet to be clarified. During a review of noncancerous endometrial lesions in postmenopausal women, we found that mucinous endometrial glands showed variable degrees of epithelial changes that ranged from the formation of simple tubular glands to the formation of complex glands with papillary tufts, and some of the glands with papillary tufts were architecturally similar to low-grade mucinous adenocarcinomas. Based on histological similarities, we have postulated that mucinous metaplasia could be a precursor lesion of mucinous adenocarcinoma. To explain the pathogenetic significance of endometrial mucinous metaplasia, we analyzed the immunohistochemical expression of ER, PR, MKI67, PTEN, b-catenin, P16 INK4A , TP53, and PAX2 in 21 endometrial mucinous metaplasias, screened for KRAS (n ¼ 16) and PTEN (n ¼ 14) mutations, and compared expression patterns between samples with simple mucinous glands, those with complex glands having intraglandular papillary tufts, and endometrioid adenocarcinomas. Compared with the surrounding flat mucinous epithelium and simple mucinous metaplasia, the intraglandular papillary tufts associated with papillary mucinous metaplasia were characterized by selectively decreased expression of PAX2 (P ¼ 0.029) and PR (Po0.001), and overexpression of P16 INK4A (P ¼ 0.014). There were no significant differences in the levels of expression of ER, PTEN, b-catenin, TP53, and MKI67 between the two groups. In contrast with endometrioid adenocarcinomas, rates of MKI67 proliferation were very low in both groups. Mutations in KRAS were identified in 89% of cases with papillary mucinous metaplasia, in contrast to 14% in simple mucinous metaplasia (P ¼ 0.001). No PTEN mutations were observed in either of the two groups. In conclusions, immunohistochemical and molecular genetic profiling suggest that papillary mucinous metaplasia is a possible precancerous lesion in a subset of endometrial carcinomas. Modern Pathology (2012Pathology ( ) 25, 1496Pathology ( -1507 doi:10.1038/modpathol.2012; published online 6 July 2012Keywords: endometrium; mucinous; mucinous metaplasia; papillary metaplasia; PAX2; P16 INK4A ; senescence Endometrial carcinoma is classified into two major groups, types I and II, according to clinicopathological features and molecular pathogenetic mechanisms. Most type I tumors are characterized by an endometrioid histology and are frequently associated with PTEN mutations, whereas type II tumors show a serous histology and are frequently associated with the altered expression of TP53 tumor-suppressor genes. Endometrial hyperplasia and endometrial intraepithelial carcinoma are thought to be precursor lesions of type I and II endometrial carcinomas, respectively. However, this simplified classification and their precursor lesions cannot explain the pathogenesis of all endometrial carcinomas.Mucinous adenocarcinoma, an uncommon type of endometrial adenocarcinoma comprising o10% of endometr...

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Section: Discussionmentioning

confidence: 99%

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

et al. 2012

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“…Although all proteins are widely expressed, KRAS is ubiquitously expressed in almost all cell types and shown to be vital for normal mouse development [Johnson et al, 1997]. In contrast, mouse model studies have demonstrated HRAS and NRAS are not as critical [Malumbres and Barbacid, 2003]. Ras is activated by diverse extracellular stimuli including receptor tyrosine kinases, cytokine receptors, Gprotein-coupled receptors, and extracellular matrix receptors (integrins).…”

Section: Discussionmentioning

confidence: 99%

HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy

Estep

Tidyman

Teitell

et al. 2005

American J of Med Genetics Pt A

165

157

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Costello syndrome (CS) is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies, and a predisposition to develop neoplasia. Based on similarities with other cancer syndromes, we previously hypothesized that CS is likely due to activation of signal transduction through the Ras/MAPK pathway [Tartaglia et al., 2003]. In this study, the HRAS coding region was sequenced for mutations in a large, well‐characterized cohort of 36 CS patients. Heterogeneous missense point mutations predicting an amino acid substitution were identified in 33/36 (92%) patients. The majority (91%) had a 34G → A transition in codon 12. Less frequent mutations included 35G → C (codon 12) and 37G → T (codon 13). Parental samples did not have an HRAS mutation supporting the hypothesis of de novo heterogeneous mutations. There is phenotypic variability among patients with a 34G → A transition. The most consistent features included characteristic facies and skin, failure to thrive, developmental delay, musculoskeletal abnormalities, visual impairment, cardiac abnormalities, and generalized hyperpigmentation. The two patients with 35G → C had cardiac arrhythmias whereas one patient with a 37G → T transversion had an enlarged aortic root. Of the patients with a clinical diagnosis of CS, neoplasia was the most consistent phenotypic feature for predicating an HRAS mutation. To gain an understanding of the relationship between constitutional HRAS mutations and malignancy, HRAS was sequenced in an advanced biphasic rhabdomyosarcoma/fibrosarcoma from an individual with a 34G → A mutation. Loss of the wild‐type HRAS allele was observed, suggesting tumorigenesis in CS patients is accompanied by additional somatic changes affecting HRAS. Finally, due to phenotypic overlap between CS and cardio‐facio‐cutaneuos (CFC) syndromes, the HRAS coding region was sequenced in a well‐characterized CFC cohort. No mutations were found which support a distinct genetic etiology between CS and CFC syndromes. © 2005 Wiley‐Liss, Inc.

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“…In addition to the recent data on NRAS as a potential target, preclinical and clinical data suggest that: (1) in BRAF-mutated melanoma patients, a concomitant baseline mutation in the upstream NRAS oncogene may result in early lack of clinical benefit to BRAF inhibitors; (2) RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. 8 Hence, testing for NRAS may be an integral part in the assessment of metastatic melanoma patients.…”

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confidence: 99%

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

et al. 2015

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Testing for NRAS is now integral part in the assessment of metastatic melanoma patients because there is evidence that NRAS-mutated patients may be sensitive to MEK inhibitors, and RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. This study evaluated the sensitivity and specificity of immunohistochemical analysis using an N-Ras (Q61R) antibody to detect the presence of the NRASQ61R mutation in melanoma patients. A total of 98 primary cutaneous melanomas that have undergone examination of NRAS mutation were retrieved from a multicentric database. Formalin-fixed and paraffin-embedded melanoma tissues were analyzed for BRAF and NRAS mutations by independent, blinded observers using both conventional DNA molecular techniques and immunohistochemistry with the novel anti-human N-Ras (Q61R) monoclonal antibody (clone SP174). The antibody showed a sensitivity of 100% (14/14) and a specificity of 100% (83/83) for detecting the presence of an NRASQ61R mutation. Of the NRAS-mutated cases, none of the non-Q61R cases stained positive with the antibody (0/7). There were three cases with discordant NRAS mutational results. Additional molecular analysis confirmed the immunohistochemically obtained NRAS result in all cases, suggesting that a multiple analytical approach can be required to reach the correct sample classification. The reported immunohistochemical method is an accurate, rapid, and cost-effective method for detecting NRASQ61R mutation in melanoma patients, and represents a valuable supplement to traditional mutation testing. If validated in further studies, genetic testing would only be required for immunohistochemistry-negative patients to detect non-Q61R mutations.

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RAS oncogenes: the first 30 years

Cited by 1,591 publications

References 114 publications

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

Papillary mucinous metaplasia of the endometrium as a possible precursor of endometrial mucinous adenocarcinoma

HRAS mutations in Costello syndrome: Detection of constitutional activating mutations in codon 12 and 13 and loss of wild‐type allele in malignancy

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

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