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The Ras Gene02:38

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
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Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
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The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Germline and sporadic cancers driven by the RAS pathway: parallels and contrasts.

V Dunnett-Kane1, E Burkitt-Wright2, F H Blackhall3

  • 1Manchester University NHS Foundation Trust, Manchester, UK.

Annals of Oncology : Official Journal of the European Society for Medical Oncology
|April 3, 2020
PubMed
Summary

Mutations in RAS pathway genes drive both cancer and developmental disorders called RASopathies. Understanding differences in mutation types between sporadic and germline cancers could improve targeted therapies.

Keywords:
Costello syndromeNoonan syndromeRASRASopathyneurofibromatosis type 1

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Area of Science:

  • Oncology
  • Genetics
  • Developmental Biology

Background:

  • Somatic mutations in RAS and NF1 genes are key drivers of cancer.
  • These same genes are implicated in developmental disorders known as RASopathies.
  • RASopathies include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, and others.

Purpose of the Study:

  • To investigate the distinct mutational patterns observed in sporadic cancers versus RASopathy-associated cancers.
  • To explore the reasons behind the differing histological origins of cancers arising from sporadic mutations versus germline variants in RAS pathway genes.
  • To inform the development of targeted therapies for both sporadic and germline cancers linked to the RAS pathway.

Main Methods:

  • Comparative analysis of mutation subtypes and locations in sporadic cancers and RASopathies.
  • Review of existing literature on RAS pathway genetics in cancer and developmental disorders.
  • Correlation of genotypic differences with phenotypic outcomes (cancer type and origin).

Main Results:

  • Significant differences exist in mutation subtypes between sporadic Ras-driven cancers and RASopathy-associated cancers.
  • Germline variants in KRAS and NRAS are seldom found at common somatic mutation sites (codons 12, 13, 61), unlike in sporadic cancers.
  • Costello syndrome presents an exception, with frequent germline variants in HRAS codons 12 and 13.

Conclusions:

  • The distinct mutational landscapes in sporadic versus germline RAS pathway alterations contribute to differences in cancer development and histology.
  • Understanding these genotypic-phenotypic correlations is crucial for advancing precision medicine in oncology.
  • Further research into RAS pathway genetics can guide the development of novel therapeutic strategies for a range of cancers.