It has been my practice every summer for many years to take on one or two high school or college students in my research group. Aside from working on an interesting project, hanging out with other students and fellows (and me), they attend my weekly clinic where they get to see what cancer is like, always of course with the permission of the patients. The students enjoy and are excited for the experience. The patients actually love the attention (usually) and will ask the students where they go to school, what they want to be and tell about their own children.
This summer one of the students is particularly enthusiastic and hard-working as well. He appreciates the clinical milieu and patients. One week in clinic, my fellow presented a new patient, a man in his 30s with prolonged abdominal discomfort who proved to have familial adenomatous polyposis (FAP), a rare genetic disorder. The patient’s father had the syndrome as well. I see many colorectal cancer patients, so I see more FAP than most, but I commented that I had not seen a case of FAP in several years (remarkably we had another case four weeks later). My summer student said, in the tone I think Lisa Sanders might use, “Wow—I have never seen a case of FAP before!”
I must confess that the thrill of seeing a “great case” has never left me since the third year of medical school, even after decades of practice. And it is no great honor to be a great case—in fact, it is usually a sad appellation. Nonetheless, we can and should appreciate the myriad ways in which God and nature can operate, not only with the wonders of normal physiology, but also with the astonishing wonders of pathophysiology.
FAP is a rare genetic disorder that arises from a mutation in the APC (adenomatous polyposis coli) gene that is located on chromosome 5. As with other similar low-frequency, high-penetrance genes, such as BRCA1/2, APC is a tumor suppressor gene, which means that two mutations on both alleles (chromosome pairs) are necessary for it to express its effects. A germline mutation in this gene is present in about 1 in 10,000 or 15,000 population, and it is estimated that the genetic mutation arose spontaneously in approximately 25% of those who present with the syndrome. Parenthetically, there is also a specific mutation at position 1307 in the APC gene that is present in approximately 6% of Ashkenazi Jews and that doubles the risk of colorectal cancer and other cancers; this mutation has no association with FAP.
To appreciate the effects of the APC mutation, we have to recall the significance of the adenoma-carcinoma sequence, i.e., the adenomatous polyp (adenoma) is the precursor lesion to colorectal cancer (and actually to small bowel cancer as well). Under normal circumstances in Western societies, about 25-30% of average-risk adults will have an adenoma on colonoscopy, and their removal by screening will eliminate the risk of progression to malignancy; this is the rationale of colon cancer screening.
Individuals with FAP develop hundreds or thousands of adenomas in their colorectum; their colons appear carpeted with these lesions. The adenomas do not seem to be different than your run-of-the-mill adenoma; it is simply the overwhelming quantity that is amiss. But if we consider that in a normal individual there is a risk that his/her adenoma may progress after several years to cancer if left in place, we need to multiply that risk by 1,000 for an FAP patient given the number of polyps in his/her bowel. As a consequence, the risk of colorectal cancer in such an individual is near 90% by age 40. The small bowel is also loaded with these polyps, and so there is a 6% risk of small bowel cancer as well.
How can we deal with this? Most such patients must ultimately come to a proctocolectomy at a relatively early age so as to prevent the occurrence of a cancer that has the opportunity to metastasize. That was the fate of our patient with FAP who had undergone this procedure.
There are also guidelines for screening the rest of his luminal GI tract—the stomach and small bowel—to prevent or detect cancer early. The APC gene mutation also puts one at risk for thyroid cancer (go figure!) and so he will require monitoring of his thyroid for the future. Other tumors are also increased and require surveillance—a genetic counselor is required for a detailed assessment.
And let us not forget his children and siblings. They will need testing, as 50% of them may inherit the same gene and require future surveillance as well. As I write this, the genetic counselors at our Cancer Center are hot on their trail.
Yes, a great case—but one where the advances of molecular genetics, gastroenterology, surgery, oncology, clinical genetics and genetic counseling have given a good future to a family, and yet one more way in which the discoveries of Watson and Crick in 1953 have borne fruit 70 years later.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
