Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations

Zenker, Martin; Lehmann, Kerstin; Schulz, Anna; Barth, H.; Hansmann, Dagmar; Koenig, Rainer; Korinthenberg, Rudolf; Kreiß-Nachtsheim, Martina; Meinecke, Peter; Morlot, Susanne; Mundlos, Stefan; Quante, Anne S.; Raskin, Salmo; Schnabel, Dirk; Wehner, Lore; Kratz, Christian P.; Horn, Denise; Kutsche, Kerstin

doi:10.1136/jmg.2006.046300

Cited by 178 publications

(182 citation statements)

References 32 publications

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“…In 35 CFC patients showing mutations in BRAF, KRAS and MEK-1, and MEK-2, approximately 40% presented wrinkled palms and soles, hyperpigmentation, and joint hyperextension, characteristics frequently seen in CS but not in CFC syndrome. Zenker et al (2006) described two infants with typical findings of CS presenting different mutations in the KRAS gene. They both presented failure to thrive, developmental delay, characteristic facies, and skin and cardiac anomalies.…”

Section: Discussionmentioning

confidence: 99%

Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene

Bertola

Pereira²,

Brasil

et al. 2007

J Hum Genet

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Section: Discussionmentioning

confidence: 99%

Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene

Bertola

Pereira²,

Brasil

et al. 2007

J Hum Genet

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“…The KRAS mutations are responsible for the synthesis of permanently active KRAS protein (23) and are mostly concentrated on 12 and 13 codon of the gene (17). Since activating mutations in the KRAS gene are found in 30-40% (17) of colorectal tumors, our laboratory has introduced an RT-PCR-based method (CE-marked diagnostic kit TheraScreen K-RAS Mutation Kit) to identify patients suitable for therapy with anti-EGFR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…The KRAS mutations represent an early event in the development and progression of colorectal cancer (20)(21)(22). The protein product of mutated KRAS gene has an increased binding affinity for GTP, causing accumulation in the active GTP-bound state by impairing intrinsic GTPase activity and conferring resistance to GTPase-activating proteins (23). The signal transduction therefore no longer runs via EGFR, resulting in the fact that patients with KRAS mutations on codon 12 and 13 have poor response to therapy with anti-EGFR inhibitors.…”

Section: Inroductionmentioning

confidence: 99%

KRAS mutations in Slovene patients with colorectal cancer: frequency, distribution and correlation with the response to treatment

Ličar

Cerkovnik²,

Ocvirk³

et al. 2010

Int J Oncol

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Abstract. KRAS mutations are proved as a predictor of response to EGFR-targeted therapies for patients with metastatic colorectal cancer. For identifying the wild-type KRAS (wt-KRAS) responder subset of patients who will benefit from novel agents our laboratory has introduced the TheraSreen K-RAS Mutation Kit ® an allele-specific RT-PCR based assay. Our aim is to describe the validation procedure of this method in our laboratory, determine the portion of colorectal cancer patients with wt-KRAS status, and assess the prognostic power of mutational status for the anti-EGFR therapy outcome in colorectal cancer patients. In this study 302 samples from 273 patients with metastatic colorectal cancer were tested for 7 most common mutations on codon 12 and 13 of the KRAS gene. We used HT-29 and CCL-247 cell lines to determine the sensitivity of the method for different proportions of tumor cells in the sample. We determined that 2% of cells carrying a KRAS mutation must be present in the sample for an undisputable detection of mutated signal using the LightCycler Adapt Software. Among the tested patients 54.5% had a wt-KRAS genotype and 45.5% had a mutated KRAS genotype. The p.Gly12Asp was the most common detected mutation (38.5%). Among the cetuximab therapy responders, 85.7% had a wt-KRAS genotype. We have shown that the RT-PCR method introduced to discriminate between anti-EGFR therapy responders and non-responders is efficient, reliable and quickly applicable. The ratio of mutated versus wt-KRAS patients in our study is similar to ratios reported by other authors, as is the high correlation between wt-KRAS genotype and response to cetuximab therapy. Nevertheless the selection of patients for treatment solely on the basis of KRAS status is not perfect due to the fact that some responders are among the patients with mutated KRAS and some non-responders among the wt-KRAS patients.

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“…In 2005, de novo heterozygous missense mutations in HRAS were found to be responsible for Costello syndrome [1,14,17,26]. Somewhat later KRAS mutations were discovered in less than 2% of PTPN11-negative Noonan patients [6,43,54] and recently mutations in the GEF SOS1 have been reported to account for approximately 20% of PTPN11-negative Noonan syndrome patients [40,49]. Finally, in CFC syndrome, mutations in KRAS, as well as BRAF, MEK1 and MEK2 were found [38,41].…”

Section: Introductionmentioning

confidence: 99%

“…In 2006, KRAS mutations were found in less than 2% of Noonan syndrome patients [6,43,54]. The phenotype associated with KRAS mutations seems to have a broad range varying from mild to severe Noonan syndrome with features of CFC syndrome and Costello syndrome.…”

Section: Noonan Syndrome (Omim 163950)mentioning

confidence: 99%

What’s new in the neuro-cardio-facial-cutaneous syndromes?

Denayer

Legius

2007

Eur J Pediatr

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The RAS-MAPKinase pathway is a signal transduction cascade which has been studied extensively during the last decades for its role in human oncogenesis. Activation of this cascade is controlled by cycling of the RAS protein between an inactive and an active state and by phosphorylation of downstream proteins. The signalling cascade regulates cell proliferation, differentiation and survival. Disturbed RAS signalling in malignancies is caused by acquired somatic mutations in RAS genes or other components of this pathway. Recently, germline mutations in genes coding for different components of the RAS signalling cascade have been recognized as the cause of several phenotypically overlapping disorders, recently referred to as the neuro-cardio-facial-cutaneous syndromes. Neurofibromatosis type 1, Noonan, LEOPARD, Costello and cardiofaciocutaneous syndromes all present with variable degrees of psychomotor delay, congenital heart defects, facial dysmorphism, short stature, skin abnormalities and a predisposition for malignancy. These findings point to important roles for this evolutionary conserved pathway in oncogenesis, development, cognition and growth. Conclusion: it has become obvious in recent years that the neuro-cardio-facial-cutaneous syndromes all share a common genetic and pathophysiologic basis. Dysregulation of the RAS-MAPKinase pathway is caused by germline mutations in genes involved in this pathway. Undoubtedly more genes causing related syndromes will be discovered in the near future since there are still a substantial number of genes in the pathway that are not yet associated with a known syndrome. Protein-tyrosine phosphatase, nonreceptor-type 11 Eur J Pediatr (2007) 166:1091-1098 DOI 10.1007 Human genes and proteins are written in capital letters; murine genes and proteins in small letters. Genes are written in italic, proteins are written straight.

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Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations

Cited by 178 publications

References 32 publications

Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene

Further evidence of genetic heterogeneity in Costello syndrome: involvement of the KRAS gene

KRAS mutations in Slovene patients with colorectal cancer: frequency, distribution and correlation with the response to treatment

What’s new in the neuro-cardio-facial-cutaneous syndromes?

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