New Series to Explore Cancer Genetic Issues

February 1, 1997

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.

The familial aggregation of cancer has piqued the curiosity of physiciansfor more than two millennia. Most explanations for this aggregation werebased upon environmental hypotheses, such as diet, solar radiation, habitpatterns, and cultural practices, as well as occupational exposures. Onrare occasions, ancients and now, more frequently, contemporaries havesuggested that genetics might provide an important causal explanation forfamilial cancer.

This centurys' old question, Is cancer hereditary? has been confirmedbeyond any doubt during the past decade, thanks to a series of landmarkmolecular genetic discoveries of cancer-predisposing genes.

These so-called cancer genes may lead to cancer as a result of threemajor etiologic events: (1) activation of oncogenes; (2) inactivation oftumor-suppressor genes; and (3) mutation of the DNA mismatch repair genes(hMSH2, hMLH1, hPMS1, hPMS2), which predisposes patients to hereditarynonpolyposis colorectal cancer (HNPCC), subsequently referred to as theLynch syndromes.

These molecular genetic studies make it possible to determine at birthan individual's lifetime risk for certain cancers. This means that a high-riskfamily member, with appropriate genetic counseling, can be informed byhis or her physician about the particular cancer-predisposing gene thatthe individual received at conception.

The DNA information will enable the patient's physician to describethe individual's predisposition to develop cancer onset and certain extra-cancerphenotypic features such as multiple colonic adeno-mas, congenital hypertrophyof the retinal pigment epithelium, and osteomas in familial adenomatouspolyposis.

Other extra-cancer phenotypic features associated with cancer-predisposinggenes include multiple mucosal neuromas, ganglioneuromas of the gastrointestinaltract, and the marfanoid habitus in the multiple endocrine neo-plasia (MEN)syndrome (type IIb, type III), also referred to as multiple mucosal neuromasyndrome.

In certain circumstances, even the survival advantage conferred by theparticular germ-line mutation, such as that for colorectal carcinoma inthe Lynch syndromes, may be predicted.

Is Cancer Prevention Possible?

The discovery of the molecular genetic basis for an increasing numberand variety of hereditary cancers is clearly one of the most momentousmedical stories of the decade. It has revolutionized cancer medicine andmade available the potential for extraordinary new horizons for genomicscience.

Indeed, this molecular genetic revolution likely will lead to the developmentof agents that can prevent cancer by (1) replacing those chemical factorsthat are lost to the cell when tumor-suppressor genes are inactivated or(2) blocking the cancer-predisposing factors that are produced when oncogenesare activated. Even the metastatic process may be prevented once the moleculargenetic basis for tumor angiogeneses and other critical events is moreclearly elucidated.

This newfound cancer genetic information has led to controversy surroundingits use in the clinical setting. Some in the genetic, medical, legal, andethics community have raised serious concern about the clinical applicationof DNA testing, particularly as this knowledge may impact upon mattersof confidentiality, insurance and employer discrimination, and the patient'sown well-being, ie, the fear and anxiety that may accompany disclosureof DNA findings.

This genetic information explosion has occurred so rapidly that it hasoutpaced 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 ostrichapproach? Clearly our patients won't allow this! The public, driven byalmost daily exposure to these scientific advances in the lay media, isdemanding that they reap any possible benefits from this DNA knowledge.

From the medical standpoint, this knowledge should compel us to develophighly targeted surveillance and management plans that can be melded tothe natural history of the differing hereditary cancer syndromes resultingfrom different germ-line mutations. In certain circumstances, the cancercan be prevented through surgical prophylaxis.

Perhaps in the physician's and the patient's mind, the most frequentlyasked question is, How can we use this molecular genetic knowledge to enhancethe diagnosis and control of cancer?

Equally important questions that patients and clinicians often ask pertainto the benefits and limitations of DNA testing, particularly the many unknownoutcomes of ensuing interventions: Who should offer DNA testing? Who shouldbe tested? When should testing be offered? What laboratories are proficientin this testing? Should testing be confined to members of cancer pronefamilies? Do the benefits outweigh the risks? Can the confidentiality ofDNA results be secure? Should this information be made available to employersor insurance carriers?

The timeliness of these vexing concerns has provided us with the stimulusto organize a series of commentaries for Oncology News International inan attempt to update this knowledge base and provide appropriate explanationsabout 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 aspectsof certain of these clinical and molecular genetic advances. We greatlyappreciate the time and commitment of these colleagues who, over the comingmonths, will be sharing with us the knowledge they have gained throughtheir painstaking research.