Case Studies - Hereditary Colon Cancer

Genetic Discoveries Offer Hope for Prevention

Case 1: Beth M.'s father died of colon cancer, as did her grandmother. Now two of her brothers, both in their 40s, have been diagnosed with colon cancer. Beth, age 37, feels a curse is hanging over her family and is worried about her future and that of her children.

Case 2: Paul C. was 35 when his doctor told him the grim news: He had advanced colon cancer. As far as he knew, Paul had no family history of the disease. But after checking, Paul learned that several aunts and uncles had died of colon cancer at an early age.

Further research revealed that some members of both Beth and Paul's families carried an altered gene, passed from parent to child, that predisposes them to a form of inherited colon cancer, known as hereditary nonpolyposis colorectal cancer (HNPCC). Sometimes difficult to diagnose, HNPCC is believed to account for one in six of all colon cancer cases.

Cancers arise from a multistep process, which involves the interplay of multiple changes, or mutations, in several different genes, in combination with environmental factors such as diet or lifestyle. In the most common, noninherited forms of cancer, the genetic changes are acquired after birth. But individuals who have an hereditary risk for cancer are born with one altered gene - in other words, they are born one step into the cancer process. In hereditary nonpolyposis colorectal cancer, for instance, children who inherit an altered gene fro either parent face a 70 to 80% chance of developing this disease, usually at an early age. Women also face a markedly increased risk of uterine and ovarian cancer.

Though scientists had known for years that an altered gene was to blame for this hereditary colon cancer, finding it was tricky for they had few clues as to where, on any of the 23 pairs of chromosomes, the gene might reside. Finally, in the spring of 1993, using tools emerging from the Human Genome Project, an international team tracked the gene to a region of chromosome 2. Seven months later, two teams zeroed in on the culprit. Just three months after that, they had identified a second gene on chromosome 3 also at work in HNPCC. Together, these genes account for most cases of this inherited cancer.

These discoveries offer a view of how the Human Genome Project is likely to transform medicine by opening up new approaches to prevention. The earliest beneficiaries will be those families facing a very high risk of colon cancer. First, for those who choose to take it, will come a simple blood test to determine who in these cancer-prone families does or does not carry the altered genes. The consequences could be enormous, for as many as 1 in 200, or 1 million Americans, may carry one or the other of th ese altered genes.

Individuals found to carry an altered gene would likely be counseled to adopt a high-fiber, low-fat diet in the hope of preventing cancer. They would also be advised to start yearly examinations of the colon at about age 30. Such exams should help physicians detect any benign polyps, wart-like growths on the colon, early in the disease process, and then remove them before they turn malignant. For those individuals who turn out not to carry the altered genes, the diagnostic test may be a huge relief, removing the fear they have lived under and sparing them the need for frequent colonoscopies.

Despite the life-saving potential of such diagnostic tests, numerous issues need to be resolved before they are introduced into general medical practice. Genetic testing is not so simple as drawing blood and telling someone the results. For one thing, the best way to test large numbers of individuals is by no means clear. In deciding whether or not to be tested, individuals need information not only about the disorder and its risk, but also about the test and its limitations. Equally important, genetic testing must be accompanied by counseling to help people cope with information about their future risk, whatever the oucome of the test. Those who test positive and who are trying to decide what course to pursue will need to know how effective various strategies, such as frequent colonoscopy and polyp removal, actually are at preventing colon cancer.

Definitive answers are still lacking for these questions. Broader, societal issues arise as well, such as how to protect the confidentiality of genetic information and ensure that it is not used to discriminate against individuals in employment or insurance.

Even before these colon cancer susceptibility genes were discovered, the Human Genome Project had begun planning pilot studies to address these and other questions about testing for cancer risk. It is important that these questions be answered now, before widespread testing begins. The identification of genes involved in hereditary colon cancer is just one in a long string of discoveries that can be expected as the Human Genome Project progresses. Careful attention to these social and ethical issues now will help prepare the public and the medical profession for the choices that lie ahead.

Depression raises colon cancer risk

For women, being depressed can raise the risk of developing colorectal cancer, a new study shows.

In the study published in the American Journal of Epidemiology, researchers from Brigham and Women's Hospital and the Harvard School of Public Health analyzed data from the Nurses' Health Study, a long-term, ongoing study involving some 121,700 female nurses.

The researchers analyzed data from 81,612 women who were cancer-free at the start of the study. On two occasions four years apart, the women were screened for depression using a five-question survey that asked, for example, how often over the previous month they had felt nervous, down or happy. Based on their symptom scores, the women were divided into four categories.

About 8% of the women were classified as having high levels of depressive symptoms. While these women were more likely than the women who reported a lower degree of symptoms to be overweight, to smoke, to be physically inactive, to eat a higher-calorie diet and to consume more red and processed meat - factors which have been linked to an increase in colorectal cancer risk - they were also more likely to take vitamins, to use aspirin and to be screened for colon cancer using colonoscopy or sigmoidoscopy.

Four years after the final screening, 400 of the participants had been diagnosed with colorectal cancer and another 966 were found to have colorectal adenomas, growths or polyps in the colon or rectum that can become cancerous.

After analyzing the data, the researchers found that women who reported the highest levels of depressive symptoms had a 43% greater risk of developing colorectal cancer than women with the lowest level of symptoms. Furthermore, they observed a "dose-response" relationship, which means that the more depressive symptoms a woman experienced, the higher her risk of developing colorectal cancer. The association was highest among women who were overweight.

The researchers found no association between depression and colorectal adenomas.
While the links between depression and cancer have been the subject of numerous investigations, the researchers say this is the first to focus exclusively on the relationship between depression and colorectal cancer. But the researchers add that more research is required to probe the mechanisms behind the apparent association.