Magdalena M. Jurkiewicz

1st Year Medical Student

Department: School of Medicine

Graduate Program: TBD

Advisor: Michael Zhang (rotation)

Abstract (undergraduate):

Advisor: Dr. Josephine Hoh, Division of Chronic Disease Epidemiology, Yale University

Title:   Identification of Genetic Susceptibility Loci for Midgut Carcinoid Tumors

Carcinoid tumors of the midgut are a rare neuroendocrine tumor localized to the second portion of the duodenum, the jejunum, ileum, appendix, or ascending colon. Current understanding of the genetic mechanisms involved in tumorigenesis of midgut carcinoids is largely limited. Early diagnosis can lead to resection of the tumor and high patient survival. Nevertheless, early diagnosis of midgut carcinoids is difficult with standard measures, and most often the patient does not present for diagnosis until he or she is experiencing symptoms, at which point metastasis has occurred and likelihood of survival has decreased significantly. Consequently, identification of genetic predispositions that might lead to an increased risk could result in careful monitoring and consequently earlier diagnosis, and greater survival.

Objectives: The specific aims of this investigation were to (1) develop a study design appropriate for determining whether there are genetic susceptibility loci in individuals with carcinoid tumors of the midgut, (2) perform quality assessment of case and control DNA provided by collaborators, (3) perform whole-genome genotyping of case and control individuals for Single Nucleotide Polymorphisms (SNPs) and (4) conduct a statistical analysis of resulting data in an effort to determine disease susceptibility loci in individuals with disease.

Study Design and Methods: The study design selected for this investigation is a population-based, case-control, whole-genome association study that includes patients with small bowel carcinoids and healthy frequency-matched controls. DNA from cases and controls from two populations was analyzed. Quality assessment of case and control DNA provided by collaborators was done through gel electrophoresis. The Illumina 300K platform was utilized in whole-genome genotyping of case and control individuals for pre-selected tag SNPs. Standard statistical analyses were performed in an effort to distinguish SNPs with alleles or genotypes that are significantly associated with disease status.

Results: As a result of statistical analyses, alleles and genotypes at three SNPs (encoded as SNP #1, SNP #2, and SNP #3 for reasons of confidentiality) were found to be possibly associated with disease status in a Northern European population with homogenous disease phenotype. Genotypic odds ratios for disease status at these SNPs for the homozygous risk genotype compared to the homozygous reference genotype are as follows (with 95% confidence intervals): 13.875 (2.563,75.125) for SNP #1 and SNP #2, and 11.562 (2.057,64.995) for SNP #3. We found SNPs #1, #2, and #3 to be located in a single gene encoding an ion transporter.

Conclusions: Preliminary results will be further explored by genotyping additional individuals and by examination of the gene of interest in cases and controls through re-sequencing. The preliminary results are suggestive of a possible disease-genotype association.

Publications:
(MSTP-supported publications indicated with an *)

Cohen RN, Cohen LE, Botero D, Yu C, Sagar A, Jurkiewicz M, Radovick S (2003). "Enhanced Repression by HESX1 as a Cause of Hypopituitarism and Septooptic Dysplasia." J Clin Endocrinol Metab 88(10): 4832-4839.