Henry T. Lynch, MD

Advances in molecular genetics have evolved at such a fast pace that physicians may be bewildered about their clinical translation into patient care. However, genetic counselors, particularly those trained in cancer genetics, have been extremely helpful. The challenge to the physician, however, calls for an understanding of the natural history of hereditary cancer syndromes, which is often reflected in the pedigree. Pedigree/family history information must be compiled in sufficient detail to arrive at the most likely hereditary cancer syndrome diagnosis so that the molecular geneticist can search for the mutation. Finally, the challenge to the clinician is melding this into an accurate diagnosis, in order to provide highly targeted screening and management for high-risk patients. This article is an attempt to crystallize all of these issues in a format that will help physicians—particularly those in the oncology community—to meet this challenge effectively.

The Lynch syndrome (hereditary nonpolyposis colorectal cancer[HNPCC]), is the most common form of hereditary colorectal cancer(CRC), accounting for 2% to 7% of all CRC cases. The next most commonhereditary CRC syndrome is familial adenomatous polyposis (FAP),which accounts for less than 1% of all CRC. Lynch syndrome is ofcrucial clinical importance due to the fact that it predicts the lifetimerisk for CRC and a litany of extra-CRC cancers (of the endometrium,ovary, stomach, small bowel, hepatobiliary tract, upper uroepithelialtract, and brain) through assessment of a well-orchestrated family history.A Lynch syndrome diagnosis is almost certain when a mutation ina mismatch repair gene-most commonly MSH2, MLH1, or, to a lesserdegree, MSH6-is identified. Once diagnosed, the potential for significantreduction in cancer-related morbidity and mortality through highlytargeted surveillance may be profound. Particularly important iscolonoscopy initiated at an early age (ie, 25 years) and repeated annuallydue to accelerated carcinogenesis. In women, endometrial aspirationbiopsy and transvaginal ultrasound are important given the extraordinarilyhigh risk for endometrial and ovarian carcinoma. Thesecancer control strategies have a major impact on at-risk family membersonce they have been counseled and educated thoroughly aboutLynch syndrome’s natural history and their own hereditary cancer risk.

Breast and ovarian carcinomas pose major public health problems in most Western countries. Countless attempts have been made to better understand a patient’s lifetime risk of breast cancer. The most significant etiologic risk is increasing age, followed by family history. In addition, hormonal and reproductive factors-ie, early menarche and later age at menopause, nulliparity (and, therefore, a greater number of ovulations over the patient’s lifetime), and late age at first pregnancy (greater than age 30 years)-also increase a patient’s breast cancer risk.

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.

Multiple endocrine neoplasia type 2 (MEN-2) is known to be associated with missense mutations in the RET proto-oncogene, and specific RET mutations have been detected in families. This disease can be deadly since more than half of patients who harbor the genetic susceptibility present with metastatic medullary thyroid carcinoma. About 50% of patients affected with MEN-2 will develop pheochromocytoma (often bilateral), and 10% to 20% will develop functioning parathyroid adenomas.

Acquired susceptibility mutation--A mutation in a gene that occurs after birth from a carcinogenic insult. Allele--One of several mutational forms of a specific gene.

This paper provides an overview of the current approach to genetic counseling for cancer, using hereditary