30 Apr Knowledge Of Gene Mutation For Hereditary Carcinoid May Allow Earlier Detection
MedicalResearch.com Interview with:
Dr. Stephen Wank MD
Digestive Diseases Branch, NIDDK
National Institutes of Health, Bethesda, Maryland
MedicalResearch: What is the background for this study?
Dr. Wank: Small intestinal carcinoids are rare and difficult to diagnose because symptoms may be absent or mistaken for more common diseases. Because carcinoids usually grow slowly over several years before spreading or causing symptoms, patients often seek medical attention late with advanced, incurable disease. However, when diagnosed at an early stage, carcinoid can be surgically cured. Presently, there are no long-term effective therapies for surgically non-resectable disease. Although carcinoids occur sporadically, there have been reports of family clusters (more than one blood relative with carcinoid). Hereditary small intestinal carcinoid has not been recognized as a disease and causative genetic factors have not been identified in either sporadic cases or families with multiple affected members.
If small intestinal carcinoid occurs in families on a hereditary basis, we hypothesized that asymptomatic relatives in families with carcinoid are at a high risk of harboring an undiscovered tumor. To test this, we established a clinical research protocol at the National Institutes of Health in Bethesda, Maryland to screen asymptomatic relatives in families with at least two cases of small intestinal carcinoid in the hope of detecting their tumors at an early surgically curable stage. If successful in our endeavor, we would improve the outcome of the disease in these asymptomatic relatives and position ourselves to discover the genetic basis for their disease. Understanding the gene mutations causing small intestinal carcinoid would allow us to screen for the disease with a blood test, help us understand what causes the disease, and treat the disease with specific targeted therapies.
MedicalResearch: What are the main findings?
Dr. Wank: We found that small intestinal carcinoid tumors occur in families on a hereditary basis.
This is a new finding and important for several reasons. Establishing a hereditary basis for the disease means that asymptomatic relatives are at high risk (up to 50% chance) for either having a tumor or developing a tumor in the future. Thus it makes sense to screen asymptomatic relatives for the presence of occult tumor. In fact, we found tumors in one third of asymptomatic relatives over 50 years old. Importantly, we found disease at an early stage that could be surgically cleared in 87% of those people. Equally important, none of the 87% who were surgically cleared of their tumor has had a recurrence after an average follow-up period of 4 years and some nearly 6 years. This outcome was much better than their symptomatic relatives who were diagnosed on average with later stage disease. Patients with hereditary small intestinal carcinoid have a very similar disease compared to the sporadic (non familial) type of carcinoid except that the majority (67-83%) of patients with familial carcinoid had multiple primary intestinal tumors. If, as we believe, multiple primary small intestinal tumors are characteristic of familial disease, then familial disease might account for as much as 22-35% of what was previously considered sporadic disease.
Studying families with a hereditary basis for their disease gave us a unique opportunity to use genetic analysis methods to determine the gene mutation associated with small intestinal carcinoid. In one large family with a sufficient number of affected members, we were able to perform linkage analysis and next generation whole exome sequencing to find the first mutated gene associated with small intestinal carcinoid tumor. Unfortunately, this gene mutation was specific to this one family, but the specificity of the gene tells us that small intestinal carcinoids in other families can be associated with mutations in other genes and thus the disease is heterogeneous in origin.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Wank: It is important for physicians and patients to know that small intestinal carcinoid can run in families as a hereditary disease. As a result, patients should be aware of whether any relatives (past, present and distant) have been diagnosed with small intestinal carcinoid.
Healthcare providers should take a careful family history to determine if any relatives of their patients may have been diagnosed with small intestinal carcinoid. If there is a family history of carcinoid, patients with carcinoid-like symptoms should be screened, especially if their relative had multiple primary small intestinal tumors. If there are two cases of small intestinal carcinoid in a family, blood-related relatives should be screened for the disease.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Wank: With this knowledge, family members can be screened to determine if they carry the gene mutation. Future research should also determine the most sensitive and cost-effective methods to screen asymptomatic relatives who carry this gene mutation to determine as early as possible if they have a tumor. It is also important to determine when would be the most appropriate age to begin screening at-risk asymptomatic relatives considering both the risks and benefits associated with the screening process. Consistent with this approach, future research should aim to develop a sensitive and specific blood test to detect early stage disease in those relatives who carry the gene mutation. Armed with the knowledge of the gene mutations, such as the gene we found in one family, future research should investigate how the protein products of these genes cause the disease. With this knowledge, further investigation can lead to targeted therapies to correct or interfere in the process leading to the development of small intestinal carcinoid tumor and treat existing disease.
Citation:
Last Updated on April 30, 2015 by Marie Benz MD FAAD