Endocrine Abstracts

Background: Small intestinal neuroendocrine tumor (SI-NET) is one of the major cancer subtypes of the small bowel. Most SI-NETs locate in the terminal ileum with a high incidence of multiple synchronous primary tumors. The only essentially curative treatment of SI-NETs is complete surgical resection; however, most SI-NET patients cannot undergo surgery as they typically present with an extensive metastatic disease. Several high-throughput sequencing studies have reported low somatic mutation rates in SI-NETs. Loss of heterozygosity at chr18 is the most frequent genomic event identified, occurring in ~60% of tumors, and the only established, recurrently mutated gene is CDKN1B, altered in ~8% of tumors. A deeper understanding of the molecular mechanisms underlying SI-NETs is urgently needed for the optimal treatment of the patients.

Methods: Our sample cohort consisted of 144 well-annotated fresh-frozen tissue specimens from 23 de-identified SI-NET patients, including 85 primary tumors, 21 metastases, and 38 patient-matched normal ileum and/or whole blood specimens. Thirteen SI-NET patients had been diagnosed with multiple synchronous primary tumors. Whole-genome sequencing was used to characterize the genomic landscape of SI-NETs, and to study the potential roles of field cancerization and germline variation in their tumorigenesis.

Results: We observed lack of shared somatic variation among the synchronous primary tumors of each multifocal SI-NET patient. There was rarely any overlap between the somatic mutational profiles of unifocal SI-NETs or between uni- and multifocal SI-NETs. Our data also indicated that multiple metastases from the same patient can originate from either one or several different primary tumors. We identified altogether >250 acquired genomic alterations among the normal ileum samples of SI-NET patients when compared to their matched whole-blood specimens, all of which were also present in the patient-matched primary tumor(s). None of these alterations were recurrent among the patients. Additionally, we have identified ~100,000 recurrent germline variants with a minor allele frequency of ≥5% among the SI-NET patients. We will next assess if these variants are enriched in our patient cohort.

Conclusion: Our results indicate major genomic diversity among uni- and multifocal SI-NETs, suggesting that SI-NETs originate independently. Different metastatic dissemination patterns highlight the need to identify and carefully remove all primary tumors. SI-NETs are unlikely to arise from normal small intestine due to field cancerization based on our current data. We are also pursuing other hypotheses that could elucidate the SI-NET tumorigenesis. Finding the cause(s) of SI-NETs is essential for decisions regarding prevention, treatment, surgery, and patient outcome.

Abstract ID 23657