Genomic Landscape of High-Grade Neuroendocrine Neoplasms

This project is a multi-omics study of high grade (grade 3) neuroendocrine neoplasms across diverse organs. Genomic analysis using low-pass whole genome sequencing for copy number analysis, whole exome sequencing and whole transcriptomic sequencing using RNAseq were performed. As high grade neuroendocrine neoplasms are highly lethal with a median survival of approximately 7 months, new insights are urgently needed for better prognosis, diagnosis and management. This study focuses on gene and pathway discoveries in this cancer, and includes samples from a diverse set of organs, including the lungs, gastroenteropancreatic tract, breast, prostate, head and neck and bladder. This study was made possible by a generous donation from The Helen B. Rodde Fund.]]>
About 46 samples were selected for genomic sequencing. Samples that met diagnostic criteria for high grade neuroendocrine neoplasm per WHO criteria were independently reviewed by an additional pathologist with expertise in neuroendocrine tumors to confirm diagnosis. Additional matched normal tissue were also sequenced when available. Waiver of consent and informed consent when appropriate were obtained under the review of the institutional IRB.]]>
Neuroendocrine neoplasms (NENs) are rare epithelial cancers with neuroendocrine differentiation. Clinically, NENs are treated based on pathologic grading, with the highest being grade 3 NENs which are the most aggressive, bearing a median survival of only 7 months and a 5-year overall survival as low as 5%. As NENs are rare - accounting for only 0.5% of all newly diagnosed malignancies-grade 3 NENs are even more so, thus severely constraining our ability to understand their tumor biology and to create effective treatment. While grade 3 NENs arise most commonly from the gastroenteropancreatic (GEP) and the pulmonary systems, they can also originate from other diverse organ systems including genitourinary, head and neck, gynecologic and breast. A central question facing the field is whether these tumors, despite originating from different organs, are the same entity (given similar appearance on histology) or different. Without a deeper understanding, the current clinical approach is to treat all grade 3 NENs with the same chemotherapy (platinum and etoposide), which unfortunately prolongs survival by only a few months. To date, no whole exomic or genomic studies have been conducted on these tumors. Prior studies have been limited to grade 1 and 2 NENs in the pancreas. Published studies on G3 NENs have been restricted to selected cancer genes analyzed with immunohistochemistry or targeted sequencing panels. This study interrogates the genomic landscape of G3 NENs in an unbiased manner using a comprehensive integrated multi-omics approach that includes somatic copy number alteration (SCNA), whole exome (WES) and whole transcriptome analysis. This dataset allows for the identification of mutations, driver genes and dysregulated signaling pathways that could present diagnostic and therapeutic opportunities for these tumors.]]>