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Genetic Tests Find Mutations, NOT Disease

An accurate gene test can tell if a mutation is present, but that finding does not guarantee that disease will develop.

For example, women with the BRCA1 breast cancer susceptibility gene have an 80 percent chance of developing breast cancer by the age of 65. The risk is high but not absolute. And family members who test negative for the BRCA1 mutation are not exempt from breast cancer risk; over time, they can acquire breast cancer-associated genetic changes at the same rate as the general population.

Much remains elusive in our understanding of cancer susceptibility. Breast cancer is a good example of how incomplete a picture we have.

Most women with a family history of breast cancer DO NOT carry germline mutations in the single highly penetrant cancer susceptibility genes, yet familial clusters continue to appear with each new generation.

About 5 to 10 percent of breast cancer cases are linked to germline mutations in single, highly penetrant cancer susceptibility genes such as BRCA1 and BRCA2. Strong genetic predisposition and cancer susceptibility in these families is passed down in an autosomal dominant fashion.

Another 15 to 20 percent of breast cancers, however, are associated with some family history but no evidence of such autosomal dominant transmission. These cases are not well understood. Possibly environmental or multiple gene interactions contribute to very low penetrance of susceptibility genes, or possibly yet undiscovered mutations are involved.

Much remains unknown about the role of epigenetic factors and cancer. Epigenetic changes are reversible modifications to genes or proteins that occur in the tumor and its microenvironment. Epigenetic modifier molecules have been observed making tumor-friendly, nonmutational changes in an already confused biosystem. For example, by heavily methylating genes or promoter regions, gene activity critical to counteract a tumorís drive toward metastasis gets turned off. Or noncoding ribonucleic acids meddle in epigenetic fashion, interfering with a cellís regulation of growth or attempt to repair damage.

In addition to oncogenes and tumor suppressor genes, most cancers acquire several other key mutations that enable cancer to progress. While researchers donít yet know all the mutations involved, they have organized them in terms of their activities in support of tumor growth and metastasis. In addition to the contributions of oncogenes and mutated suppressor genes, additional genomic mutations enable the invasion of neighboring tissue, evasion of immune system detection, recruitment of a new blood supply, dissemination and targeting of new sites, and the penetration and reinvasion through new blood and tissue layers. Over time, successful metastasis occurs.

A comprehensive analysis of the cancer genome remains a daunting challenge. There is no single technology at present that will detect all the types of abnormality--deletions, rearrangements, point mutations, frameshift insertions, amplifications, imprinting, and epigenetic changes--implicated in cancer. Microarrays and gene chip analysis, however, are beginning to unveil some key genomic drivers. (Please see Molecular Diagnostics for more information.)

Many clinical trials now include genomic profiles of cancer patients as prognostic and diagnostic indicators. Genomic profiles are even used to monitor where and how the cancer genome has been hit during molecularly targeted therapies. Mining and sharing all this data should eventually help oncologists to better integrate the genotypic and phenotypic changes that occur in a biosystem during cancerís progression. This knowledge will be used to bring earlier and better interventions to cancer patients.

Date: 2015-12-24; view: 896

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