Cancer Genetics 4 Notes

CANCER GENETICS

Cause of cancer

-somatic mutations in critical growth controlling genes

-tumour suppressor genes- off switches

-oncogenes – on switches

-mismatch DNA repair genes- If DNA undergoes damage from sunlight, chemicals, cigarette smoke, the DNA repair genes rectify the damage. If DNA repair is not working mutations persist when cell reproduces.

-rare families have inherited (germline) mutations in some of those genes

Oncogenes

-oncogenes are altered forms of the normal genes proto-oncogenes- these genes cause cells to grow and divide and are tightly controlled by other genes.

Function :-the main role of proto-oncogenes is to code for proteins that allow for signal transduction pathway- complex multi-step pathway from the cell membrane, through the cytoplasm, to the nucleus

-Type of proto-oncogenes:

-Growth factors: these control transition of a cell from Go to cell cycle. Growth factors stimulate cells to grow by binding to growth factor receptors. E.g v-SIS oncogene

-growth factor receptors: some oncogenes encode for growth factor receptors with tyrosine kinase activity. These receptors span the membrane or are found in the cytoplasm. Mutations of this oncogene results in ligand independent activation

-intracellular transductor factors: E.g proteins with GTPase activity-when they bind to GTP they become active, intrinsic GTPase activity generate GDP-this inactivates the protein. Mutations in these genes result in increased GTPase activity- unrestrained growth

Mutation in the proto-oncogene- results in an ocogene that codes for a protein that is permanently active and results in the cell to keep on dividing.

1 mutation is sufficient for role in cancer development

Tumour suppressor genes

-For tumour suppressor gene to cause cancer both copies need to be mutation

-If one mutation of the tumour suppressor gene is inherited-the individual is susceptible to getting a tumour. If other copy is mutated due to environment individual develops tumour.

-The ‘2-hit Hypothesis’ in terms of tumour suppressor genes was proposed by Knudson who studied a lage number of retinoblastoma cases. He found:

-a cell can initiate a tumour only when it contains two mutant alleles

-individuals in normal population require two somatic mutations to initiate a tumour

-individuals who inherit a germline mutation in a tumour suppressor gene only require one further somatic mutation to generate a tumour

-these individuals tend to develop tumours at a younger age and at multiple sites compared to the general population.

CANCER PREDISPOSITION SYNDROMES

Familial breast cancer

-incidence of breast cancer is Caucasian women in UK = 1 in 8 : 90-95% is sporadic, 5-10% is genetic

-in individuals with a genetic predisposition to developing a particular type of tumour tend to cancer earlier than the general population –penetrance

-the genes predisposing to familial breast cancer are BRACA1/BRACA2 (account for most of the genetic cases) P53

-linkage analysis in families with breast cancer showed that disease was segregated with polymorphic marker associated with chromosome -BRACA1: chromosome 17q / BRACA2: chromosome 13q – these genes act as DNA repair genes

-How to diagnose a genetic familial breast cancer- Obtain a thorough family history, consult the risk curves and calculate the likelihood the cancer is caused by a breast cancer predisposition gene: ‘essay question’ –

-lots of people (1^st and 2^nd degree) affected by breast and/ ovarian cancer in the family- greatly increases the recurrence risk and more likely to be due to a breast cancer gene

-age of diagnosis is <50

-bilateral breast cancer

-breast and ovarian cancer in the same individual

-male breast cancer

-Inheritance pattern- most likely to be dominant inheritance

-Jewish ancestry

-Manchester scoring system: determines the likelihood of identifying BRCA1/BRCA2 MUTATIONS based on family history information

GENETIC TESTING

Purpose: early detection of cancer , appropriate treatment- change in lifestyle, diet, drug therapy, screening

-to clarify the risk- blood from a ...

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