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theses

Neuroendocrine tumors (NETs) are a rare, slow growing and biologically poorly understood presenting unique clinical challenges. The majority of NETs are localized to the gastrointestinal tract (predominately small intestinal and pancreas) and lung. NETs are well differentiated and the majority follows a benign course. However, these benign tumors can transform to malignant disease and results in adverse clinical outcome with few therapeutic options. The WHO classification of NETs has evolved over the last two decades but still lack clinical biomarkers for NETs stratifications. With greater awareness of NETs in clinic and improvement in diagnostic imaging techniques, the incidence rate of NETs has increased. Despite the increased incidence rate, the biological knowledge of these NETs is limited.

The central theme of this thesis was to provide greater insights into NET biology including clinically relevant molecular subtypes, tumorigenesis pathways, tumor cell-of-origins and biomarkers for translation research. Specifically, the thesis focuses on genomic characterization of three major NET types: pancreatic NETs, lung carcinoids and small intestine NETs. The projects discussed in chapter 2, 3 and 4 involved the integration of genomics dataset (DNAseq, RNAseq and DNA CpG methylation) accompanied by clinical information.

In Chapter 2, I discuss the results for pancreatic NETs (PanNETs). We identified two molecular subtypes of PanNETs with distinct genotype and clinical phenotypes. PanNETs with mutation in ATRX, DAXX or MEN1 gene (A-D-M mutant subtype) have adverse clinical outcome and resemble the gene expression profile of pancreatic alpha cells. We identified novel gene signature and biomarkers that differentiate PanNETs genotypes and gained an enhanced biological understanding of PanNETs from the cell lineage viewpoint.

In Chapter 3, I discuss the results for lung carcinoids. We identified three novel molecular subtypes (LC1, LC2, and LC3) with distinct clinical phenotypes. The recurrent mutations we identified were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%) (MEN1, ARID1A, KMT2C and KMT2A) as well as DNA repair (17.2%) pathways. We found two biomarkers, ASCL1 and S100 that can stratify the three subtypes. MEN1 mutations were found to be exclusively enriched in subtype LC2. Subtype LC1 and LC3 is predominately found at peripheral and endobronchial lung respectively. Subtype LC3 is diagnosed on average 10 years earlier than LC1 and LC2.

In Chapter 4, I discuss the results for small intestine NETs. We identified two (SINET-A and B) molecular subtypes of SI-NETs using gene expression and genetic dataset with distinct cell-of-origin signature. We identified one copy loss of chromosome 18 (chr18) in 85% (22 of 26) of subtype SINET-B while subtype SINET-A is diploid for chr18. We found that SINET-A subtype may originate from TPH1-/REG4- neuroendocrine cells of the small intestine and SINET-B from EC cells, which are TPH1+/REG4+. Gene expression profile of two potential biomarkers (LMX1A and ONECUT2) was found to stratify the two subtypes.

Taken together, this research demonstrates the clinically relevant molecular subtypes of NETs with distinct molecular genotypes, cell linage and clinical phenotypes. This molecular classification of NET subtypes will improve NETs stratification, and may facilitate the molecular understanding of their pathogenesis and improve clinical management.

ETD_9452

Ph.D.

Includes bibliographical references

by Saurabh V. Laddha

doi:10.7282/t3-4s9m-dz39

ETD doctoral

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