Genes, in which key mutations confer highly or moderately increased risks of cancer, are called cancer predisposition genes. A finding by Dr. Nazneen Rahman in the Institute of Cancer Research shows that over 100 of cancer predisposition genes identified provide important scientific insights in many areas ,particularly the mechanism of cancer causation.
Furthermore, changes in predisposition genes, each with a small effect, may underlie susceptibility to cancer. Thus, clinical use of these genes can make a substantial effect on diagnosis, prevention, and treatment of cancer. The recent advances in the next-generation sequencing hold the promise of discovering many more cancer predisposition genes.
Currently, scientists mainly work on identifying genetic variants that have a small impact on cancer risk but are common in the general population. Although each of these variations only act slightly, mutation accumulation of different genes may increase the risk of suffering cancer significantly according to multiple “hits” theory of carcinogenesis.
Genetic disposition to breast cancer
Genetic variations make an important contribution in developing breast cancer. For instance, certain mutations in the BRCA1 or BRCA2 genes greatly increase a person’s risk of developing breast cancer, identified by genome-wide linkage analysis and positional cloning. Mutational screening of genes functionally related to BRCA1 and/or BRCA2 has revealed four genes, CHEK2, ATM, BRIP1, and PALB2; mutations in these genes are rare and confer an intermediate risk of breast cancer.
Additionally, Variations in other genes, such as BARD1 and BRIP1, also increase breast cancer risk, but the contribution of these genetic changes to a person’s overall risk appears to be much smaller. Despite these discoveries, most of the familial risk of breast cancer remains unexplained.
Genetic disposition to colorectal cancer
Genetic variations can affect the risk of developing colorectal cancer. The 2 major types of genomic instability found in colorectal cancers are chromosomal instability (CIN) and microsatellite instability (MSI). CIN is often associated with mutated APC. The associated familial cancer susceptibility syndromes are familial adenomatous polyposis coli, due to inherited APC mutations, and Lynch Syndrome or hereditary nonpolyposis colorectal cancer syndrome, due to inherited mutations in one of the mismatch repair genes (predominantly MLH1 and MSH2)
A large number of genetic tests are available to judge whether a person has a genetic variant that predisposes him or her to colorectal cancer, including APC, MLH1, and MSH2 mutations.
Genetic disposition to gastric cancer
The association of gastric polyps and cancers in familial adenomatous polyposis(FAP) implicates the APC gene in gastric carcinogenesis. Inactivation of the APC gene on chromosome 5q is seen in about 20% of early sporadic gastric cancers, but is predominately associated with the differentiated diffuse disease. The APC gene therefore appears to play a key role in initiation of a subset of sporadic gastric as well as colonic cancers.
Possible sites of other predisposition genes, such as tumour suppressor genes, can be identified from sites of chromosomal loss. These can be detected either cytogenetically or by loss of heterozygosity (LOH) using microsatellite markers. LOH at chromosomes 1p, 5q, 7q, 11p, 13q, 17p and 18p among others has been observed in a high percentage of gastric cancers.
Although cancer predisposition genes can be employed for clinical practice guidelines, there is also high potential for incorrect inferences and inappropriate clinical applications. Thus realizing the promise of cancer predisposition genes for science and medicine will thus require careful navigation.
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