Genetic factors

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)


Most cancers are monoclonal, i.e., a single cell accumulates sufficient mutations in key genes resulting in uncontrolled cell proliferation. Genes involved in the development of cancers fall into three categories.

Tumor suppressor genes—genes whose function is lost during carcinogenesis

Both allele copies must be inactivated before the tumor suppressor function is completely lost, resulting in the absence of normal protein product (recessive).

  • p53 gene produces a transcriptional regulator involved in cell cycle control and maintaining genomic integrity.
  • Functional mutations result in loss of growth-inhibitory mechanisms.
  • Mutations can be hereditary, i.e., germline mutations, or acquired.
  • 50% of human cancers possess p53 mutations, including carcinomas of breast, lung, pancreas, and colon, and brain tumors as well as malignancies seen in the inherited Li–Fraumeni syndrome.

Proto-oncogenes—genes whose function becomes enhanced in carcinogenesis

These usually play an essential role in controlling cell proliferation and encoding growth factors, growth factor receptors, and transcription factors. Mutations of oncogenes may impede normal regulation, resulting in uncontrolled cellular replication. Mutations in only one of the proto-oncogene alleles are needed for the mutant gene product to influence downstream events, i.e., mutations are dominant at the cellular level.

  • Ras proto-oncogene encodes a membrane-associated G protein responsible for cellular signal transduction.
  • Mutated Ras products remain activated even in the absence of the appropriate growth factor receptor signal.
  • Mutations in Ras are implicated in 30% of all cancers including melanoma, lung, and pancreas.

DNA repair genes—genes whose usual function is to carry out DNA repair

Functional mutations of DNA repair genes accelerate accumulation of mutated tumor suppressor genes and proto-oncogenes.

  • ATM gene (chromosome 11) encodes a protein involved in the detection of DNA damage, with an important role in cell cycle progression.
  • Multiple double-stranded DNA breaks lead to high rates of chromosomal rearrangements producing the syndrome of ataxia– telangiectasia associated with progressive cerebellar ataxia, increased incidence of certain malignancies such as lymphomas and leukemias, and an enhanced response to treatment with ionizing radiation.

Specific genes that confer a high probability of susceptibility to specific cancer

  • Usually highly penetrant
  • Comprise 5% of total incidence of cancers

Examples of disorders (cancer), chromosome and gene relationships

  • Retinoblastoma: 13q–RB.
  • Wilms’ tumor: 11p–WT.
  • Familial adenomatous polyposis: 5q–APC
  • Hereditary non-polyposis coli Lynch I (colon): 18q–MSH2 Lynch II [gastrointestinal (GI), genitourinary (GU)]: 2p–LCF2
  • Li–Fraumeni syndrome: 17p–p53
  • Breast/ovary: 17p–BRCA1
  • Dysplastic nevus syndrome: 1p–CMM.

Genes with modest effects that may interact with environmental factors

  • Tumor viruses expressing genes that disrupt activity of tumor suppressor genes

Genetic (somatic) mutations caused by recognizable carcinogens causing sporadic cancers

Many exogenous carcinogens cause somatic mutations, e.g., aromatic hydrocarbons and ultraviolet (UV) radiation.

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