The familial aggregation of cancer has piqued the curiosity of physicians for more than two millennia. Most explanations for this aggregation were based upon environmental hypotheses, such as diet, solar radiation, habit patterns, and cultural practices, as well as occupational exposures. On rare occasions, ancients and now, more frequently, contemporaries have suggested that genetics might provide an important causal explanation for familial cancer.
This centurys' old question, Is cancer hereditary? has been confirmed beyond any doubt during the past decade, thanks to a series of landmark molecular genetic discoveries of cancer-predisposing genes.
These so-called cancer genes may lead to cancer as a result of three major etiologic events: (1) activation of oncogenes; (2) inactivation of tumor-suppressor genes; and (3) mutation of the DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2), which predisposes patients to hereditary nonpolyposis colorectal cancer (HNPCC), subsequently referred to as the Lynch syndromes.
These molecular genetic studies make it possible to determine at birth an individual's lifetime risk for certain cancers. This means that a high-risk family member, with appropriate genetic counseling, can be informed by his or her physician about the particular cancer-predisposing gene that the individual received at conception.
The DNA information will enable the patient's physician to describe the individual's predisposition to develop cancer onset and certain extra-cancer phenotypic features such as multiple colonic adeno-mas, congenital hypertrophy of the retinal pigment epithelium, and osteomas in familial adenomatous polyposis.
Other extra-cancer phenotypic features associated with cancer-predisposing genes include multiple mucosal neuromas, ganglioneuromas of the gastrointestinal tract, and the marfanoid habitus in the multiple endocrine neo-plasia (MEN) syndrome (type IIb, type III), also referred to as multiple mucosal neuroma syndrome.
In certain circumstances, even the survival advantage conferred by the particular germ-line mutation, such as that for colorectal carcinoma in the Lynch syndromes, may be predicted.
Is Cancer Prevention Possible?
The discovery of the molecular genetic basis for an increasing number and variety of hereditary cancers is clearly one of the most momentous medical stories of the decade. It has revolutionized cancer medicine and made available the potential for extraordinary new horizons for genomic science.
Indeed, this molecular genetic revolution likely will lead to the development of agents that can prevent cancer by (1) replacing those chemical factors that are lost to the cell when tumor-suppressor genes are inactivated or (2) blocking the cancer-predisposing factors that are produced when oncogenes are activated. Even the metastatic process may be prevented once the molecular genetic basis for tumor angiogeneses and other critical events is more clearly elucidated.
This newfound cancer genetic information has led to controversy surrounding its use in the clinical setting. Some in the genetic, medical, legal, and ethics community have raised serious concern about the clinical application of DNA testing, particularly as this knowledge may impact upon matters of confidentiality, insurance and employer discrimination, and the patient's own well-being, ie, the fear and anxiety that may accompany disclosure of DNA findings.
This genetic information explosion has occurred so rapidly that it has outpaced most physicians' ability to comprehend the myriad scientific, ethical, legal, socioeconomic, and clinical nuances that embody DNA knowledge.
What are we to do about these concerns? Should we adopt the ostrich approach? Clearly our patients won't allow this! The public, driven by almost daily exposure to these scientific advances in the lay media, is demanding that they reap any possible benefits from this DNA knowledge.
From the medical standpoint, this knowledge should compel us to develop highly targeted surveillance and management plans that can be melded to the natural history of the differing hereditary cancer syndromes resulting from different germ-line mutations. In certain circumstances, the cancer can be prevented through surgical prophylaxis.
Perhaps in the physician's and the patient's mind, the most frequently asked question is, How can we use this molecular genetic knowledge to enhance the diagnosis and control of cancer?
Equally important questions that patients and clinicians often ask pertain to the benefits and limitations of DNA testing, particularly the many unknown outcomes of ensuing interventions: Who should offer DNA testing? Who should be tested? When should testing be offered? What laboratories are proficient in this testing? Should testing be confined to members of cancer prone families? Do the benefits outweigh the risks? Can the confidentiality of DNA results be secure? Should this information be made available to employers or insurance carriers?
The timeliness of these vexing concerns has provided us with the stimulus to organize a series of commentaries for Oncology News International in an attempt to update this knowledge base and provide appropriate explanations about these matters to the medical community.
The colleagues we have selected to write articles for this series have, in many cases, devoted their lifetime to the basic and clinical aspects of certain of these clinical and molecular genetic advances. We greatly appreciate the time and commitment of these colleagues who, over the coming months, will be sharing with us the knowledge they have gained through their painstaking research.