The Neklason Lab is a highly translational lab that works closely with the staff and patients in the High Risk Cancer Research, Familial Cancer Assessment Clinic and Hereditary Gastrointestinal Cancer Registry. Through better understanding key factors involved in cancer risk and progression, better prevention and treatment approaches can be developed.
Common Familial Colorectal Cancer
The presence of family history is a well-established risk factor for colorectal cancer (CRC) with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5% and genome-wide association studies have identified low penetrance common variants in the population (relative risk <2) that account for an additional 5% of colorectal cancers. This leaves greater than 15% of inherited CRCs without clear genetic definition. This undefined population is composed of both moderately penetrant genetic variants and rare “private mutations”. Identification of this next tier of unknown genetic risk factors is important because increased cancer surveillance would be justified in this population. In addition, by defining the molecular pathways involved we will gain a better understanding in the development of CRC and thus suggest targets for cancer prevention in this at-risk population. Our research population consists of CRC affected relative pairs and large multigenerational families with excess clustering of cancers. The major source of our research population is an extraordinary resource of over 15 million records that link cancer and medical records to extensive genealogies dating back to the 1800s and housed in the Utah Population Database (UPDB). In affected relative pairs and large families, known syndromes are excluded, phenotypes confirmed with medical records, and genetic analysis performed by either 1) exome sequencing with variant analysis and sharing in affected individuals and 2) evaluation of shared genomic segments using SNP genotyping, followed by targeted sequencing. Our collaborators on this project include Drs. Sean Tavtigian, Lisa Cannon-Albright, Richard Kerber, and Georgia Wiesner.
Molecular Signatures of Inherited Colorectal Cancer Syndromes
The aims of this project are to 1) define unique RNA-microarray expression signatures in normal colonic mucosa taken from patients with seven different rare inherited colon cancer syndromes 2) develop a quantitative RT-PCR-based assay to precisely measure RNA levels in normal colonic mucosa from patients with rare inherited colon cancer syndromes for use as reliable clinical diagnostic tests and 3) evaluate RNA microarray expression in normal and neoplastic colonic mucosa from patients with rare inherited colon cancer syndromes to identify molecular pathways that may be a target for chemoprevention or cancer treatment. We have successfully run Agilent 44K microarrays on 150 tissues including patient matched normal and polyp. RTqPCR was used to validate a set of 7 genes whose expression in normal colonic mucosa predicted each of the syndromes with 70% correct classification. We have also identified several molecular pathways that are important in the transition from normal to polyp tissue in the syndromes.
Molecular and Genetic Characterization of Colon Cancer Syndromes
Sometimes a family has all the features of an inherited colorectal cancer syndrome, but identification of a specific genetic change has evaded the clinical laboratory and care provider. This knowledge is important to identify what individuals in the family are at-risk of developing cancer, and defining what types of cancers require early screening. We work closely with the Hereditary Gastrointestinal Cancer Registry, the Cancer Genetics Study and the Familial Cancer Assessment Clinics at Huntsman Cancer Institute to identify the individuals who may benefit from research on their family. Our laboratory works to evaluate the DNA, RNA and proteins from these individuals and their tumors to extract clues about what genetic changes are leading to their cancer syndrome. We have identified deep intronic mutations, promoter mutations and mRNA allelic imbalances. We also are using haplotype profiles to determine individuals that descend from a common founder mutation.
Genetic Events Leading to Cancer (GELT-C)
By the time a cancer is diagnosed, the somatic tissue has acquired an enormous amount of mutations consisting of both drivers and passengers. We are interested in being able to identify when, during the cancer progression, specific genes and pathways are mutated. Genes can be involved in initiation, proliferation, invasion or metastasis. The ultimate goal is to use this knowledge to direct cancer prevention and treatment effort. The project will establish a resource of somatic DNA representing the progression of a colonic adenoma to cancer. We will be collecting FFPE biopsies of polyps greater than 10 mm representing tubular adenomas > villous adenomas > high grade dysplasia. We are collaborating with Drs. John Fang and Mary Bronner on this project.
Molecular Predictors of Missed Cancers (Jewel Smadder, PI)
The overall goal of this study is to test whether specific molecularly-defined colorectal subtypes are associated with missed and interval cancers that develop 3 to 5 years following colonoscopy. Although existing data are limited, certain pathways of colorectal cancer tumorigenesis may be associated with a greater risk of missed or interval cancer following colonoscopy. We have identified a cohort of missed colorectal cancers using Utah Population Database resources. Tumor blocks will be obtained and evaluated for specific molecular markers (CIMP, BRAF, KRAS, and MSI) and correlated with clinical data.
FAP-EST clinical trial
Efficacious chemoprevention for duodenal adenomas is an unmet clinical need in familial adenomatous polyposis patients that would reduce the morbidity from duodenectomy and risk of duodenal adenocarcinoma. Sulindac is an effective agent for reduction of colonic adenomas, but has limited impact on the duodenum. One explanation for this disparity may be higher COX-2 levels in the small bowel. Because EGFR activation increases COX-2 expression which in turn leads to reinforcement of EGFR activation and signaling, combinational inhibition of EGFR and COX-2 may lead to successful regression of duodenal adenomas. With our clinical team, we are performing a single-center, phase II, six-month-long, double-blind, placebo-controlled, randomized trial of the EGFR inhibitor erlotinib (Tarceva) and COX inhibitor sulindac in patients with a clinical or genetic diagnosis of FAP or attenuated FAP. The primary aim is to determine if the combination of sulindac (150 mg twice daily) and erlotinib (75 mg once daily) causes a significant regression of duodenal adenomas as compared with placebo. Secondary aims are to measure levels of COX-2 and EGFR molecular pathway activation in drug versus placebo endoscopic biopsies.
Genetic and Environmental Etiology of Familial Carcinoid Cancer
Carcinoids are rare neuroendocrine tumors. The majority occur in the GI tract (67%), primarily in the small intestine. Incidence of neuroendocrine tumors is 2.47 per 100,000 with the rate steadily increasing over the past 20 years. This cancer is highly familial with a 13-fold increased incidence in first degree relatives. This project is examining familial clustering of carcinoid cancers as well as environmental clustering to better understand the interaction between genetics and environment. Additionally, next-generation sequencing of families with carcinoid cancers is used to identify the genetic factors driving this risk.