Cancer: Molecular Biology
Table of Contents
Cancer is a genetic disease characterized by accumulating changes in the somatic cell genome.1
The nature of these alterations favors diminished and then finally uncontrolled cell division.
Insights into the basic molecular pathophysiology has been enhanced by the recent sequencing of the human genome and associated improvements in DNA sequencing techniques.
With respect to solid tumors, for example those characteristic of pancreatic adenocarcinoma, the transformation from normal cell physiology to malignant cell behavior depends on many genetic changes over a period of decades.
This extended timeframe offers, in principle, numerous opportunities both for detection and therapeutic intervention.1
New insights in cancer biology have been summarized:1
1. "The genomic maps are redesigning the tumor taxonomy by moving it from a histologic-to a genetic-based level.
2. The success of cancer drugs designed to target the molecular alterations underlying tumorigenesis has proven that somatic genetic alterations are legitimate targets for therapy.
3. Tumor genotyping is helping clinicians to individualize treatments by matching patients with the best treatment for their tumors.
4. Tumor-specific DNA alterations represent highly sensitive biomarkers for disease detection and monitoring.
5. Finally, the ongoing analyses of multiple cancer genomes will identify additional targets, whose pharmacological exploitation will undoubtedly result in new therapeutic approaches.
Cancer genes may be categorized into two or three groups: oncogenes, tumor-suppressor genes and stability genes.1,2
Tumor-suppressor genes naturally inhibit tumor formation; however, if this activity is diminished or prevented by mutation, tumorigenesis is favored.1
Certain locations in oncogenes tend to be the focus of mutations that result in predisposition to tumor formation.
In oncogenes mutations are typically "missense" mutations, usually affecting a single allele; as a result, they are heterozygous.
Mutations in tumor suppressor genes by contrast are usually throughout the gene, often affecting both alleles with loss of heterozygosity.
Somatic mutations, associated with malignant tumors, involve:1
insertions and deletions
chromosomal rearrangement and
changes in copy number.
As noted above, multiple genetic changes are required for the development of neoplasia.
One cancer type, colorectal cancer, exhibits this multistep process.
This process plays out over decades and appears associated with at least seven genetic events.
Within this framework, however, the inheritance of a single alter gene influences predisposition into distinct syndromes, Familial Adenomatous Polyposis (FAP) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC).
The genetic error in FAP targets the adenomatous polyposis coli (APC) gene.2
The function of the APC gene targeted is that of its "gatekeeper" activity.2
A gatekeeper gene function is to maintain an effectively constant cell number in cell populations that are renewing.
Therefore, if cell proliferation is required as a response to, for example tissue damage, the gatekeeper gene will ensure the reestablishing of the correct balance between cell division and cell death following transient proliferative response required for tissue repair.
Gatekeeper gene mutations may lead to an imbalance of cell division relative to cell death, leading to extended proliferation.
Furthermore, an intact gatekeeper gene can correct for consequences of other gene mutations, which would predispose to long-term proliferation; therefore, the gatekeeper gene can protect against other factors promoting cell proliferation.
With respect to colorectal tumors, about 50% of individuals in the "West" will develop such a tumor by the age of 70 with about 10% of these individuals manifesting progression to malignancy.2
At least 15% of colorectal tumors exhibit inherited patterns with the two best describe familial forms noted above, FAP and HNPCC.
FAP, an autosomal dominantly inherited disorder, is observed in about one in 7000 individuals.
These individuals exhibit hundreds to thousands of colorectal tumors a.k.a. adenomatous polyps (see figure above).
These tumors are typically benign; however, because of their numbers, some are likely to progress to invasive cancers (carcinomas).
FAP patients also develop with extracolonic presentation such as retinal lesions, skin desmoids, brain tumors, and osteomas.
By analyzing germline alterations in FAP patients and associated somatic changes in colorectal tumors, the involvement of the APC gene was suggested to cause FAP.
Proving causation required showing co-segregation of mutant APC alleles in affected relatives.2
Accordingly, DNA from 61 unrelated patients exhibiting adenomatous polyposis coli (APC) was analyzed for mutations in three genes: the DP1 gene, the SRP19 gene and the DP2.5 gene.4
Mutations in the DP2.5 gene has been identified as causative of APC (skip to the DP2.5 section).