Your family history provides hints about your own makeup, including diseases and conditions to which you may be susceptible. For problems caused by a single defective gene, such as Huntington’s disease or Marfan syndrome, the family history is a powerful predictor of risk. Thus, learning your family history in detail is an important part of any comprehensive assessment of your future health.
Of course, your family history has predictive limitations. Conditions found in ancestors often were due to occupational or lifestyle exposures rather than to a heritable genetic basis. And the genetic contribution to disease is often complex and multifactorial, as in heart disease and cancer, making it difficult to accurately predict risk from family history alone.
You were born with a genetic complement shared by each of the cells of your body. About 3 billion bits of information are contained in your DNA, organized into 46 chromosomes and about 20,000 individual genes. Those genes are decoded to produce proteins that make up your body structure, mediate biochemical reactions, and arrange cell replication. They are intimately tied to your body’s structure and function, growth and behavior. They help determine your body’s resistance to environmental threats, and they encode the aging process.
Errors in your inherited genome can make you more susceptible to a particular disease, two examples of which you can read about below. Thanks to the Human Genome Project and related research, we are now able to examine the sequence of specific portions of your genome to predict your susceptibility to various diseases with greater accuracy than by family history alone. And it will soon be economically feasible to determine the sequence of your entire genome, creating a catalog of information to be explored for health implications. The field of genomics is expanding at a rapid pace, helping to personalize our strategies for disease prevention and early detection, and to individualize treatments.
You start with genetically identical cells, but during life the integrity of your genome is progressively degraded by accumulated errors in the genetic code. When a cell copies itself, its own DNA is the template from which a copy is produced. But because the DNA replication process is flawed, about one in every million bits, or about 3,000 bits per cell division, are miscopied. And those errors, together with external insults to the genome from sources such as radiation and viral integration, accumulate through subsequent cell divisions.
Thus, as you age, your cells become less and less like each other and have genomes that differ progressively from the one you started life with. Most of those accumulated errors have no deleterious effect, and perhaps no single error does. But collect the wrong set of six or eight errors in the same cell and its regulatory system might be compromised, leading to rapid and uncontrolled cell division, a cancer. As you will see below, some inherited genomes are inherently more susceptible to DNA copying errors.
Breast cancer is the second most common lethal cancer in woman. In the U.S., a woman’s lifetime risk of developing breast cancer is about 13%. But in some families, many of Jewish Ashkenazi descent, that risk is 50-80%, and cancers tend to appear earlier in life.
In the early 1990s, mutations of the genes BRCA1 and BRCA2 were found to be implicated. Women carrying a single mutation of BRCA1 or BRCA2 are four to six times more likely to develop breast cancer, and they also have an increased risk of ovarian and other cancers. Men carrying a BRCA1 mutation have a 80-fold increased risk of breast cancer. Since the discovery of BRCA1 and BRCA2, other genetic mutations, most notably PALB2, have also been linked to a high likelihood of breast cancer.
Breaks in DNA occur naturally during preparation for cell division and in response to external forces such as therapeutic radiation. Those breaks disrupt gene continuity and greatly increase the likelihood of cancer. The protein products of BRCA1, BRCA2 and PALB2 constitute a built-in DNA repair mechanism that helps cells to repair broken DNA strands. Specific mutations of BRCA1, BRCA2 and PALB2 inactivate the DNA repair mechanism and increase the likelihood that cancer will develop.
Recognizing carriers of mutant BRCA1, BRCA2 and PALB2 genes who possess a DNA repair defect is critical for reducing the risk of developing cancers of the breast, ovaries and other organs. We are not yet capable of restoring normal gene function. However, intensive cancer surveillance is warranted in these individuals, and many choose more definitive measures such as organ removal.
Cancer of the colon, the second-deadliest malignancy after lung cancer, occurs in about 5% of individuals and accounts for 50,000 deaths per year in the U.S. Two familial colon cancer syndromes have been identified in which genetic mutations markedly increase the likelihood of cancer.
The first, hereditary non-polyposis colon cancer, or Lynch syndrome, is due primarily to mutation of the MSH2 or MLH1 gene. Individuals with one of these mutations have an 80% lifetime risk of developing colon cancer, and 80% of women will develop uterine cancer. MSH2 and MLH1 encode proteins that are key players in a cellular DNA editor. As you learned earlier, DNA copying is flawed. The cellular DNA editor manages to correct many of the copying errors made during DNA replication, improving the integrity of the genome. Absent this function, many more errors go uncorrected, increasing the likelihood of cancer.
A second colon cancer syndrome involves a mutation of the APC gene and results in an almost 100% cancer likelihood, usually before age 40. The APC gene encodes a tumor suppressor protein that limits the rate of cell division. When the APC gene is defective, cell replication proceeds at a much faster rate, resulting in rapid accumulation of DNA errors and eventual cancer.
Given their high likelihood of developing colon cancer, recognition of individuals with MSH2, MLH1 and APC mutations can lead to intensive surveillance for precancerous colon and uterine lesions, reducing the likelihood of cancer-related death.
Explore the intricacies of the Modern Physical’s detection and prediction methods in the links below.