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
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
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
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
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
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
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.