Abstract 46: Independent clonal origins of synchronous primary tumors in multifocal ileal neuroendocrine tumor patients
Authors: MÄKINEN NETTA , Zhou Meng , Zhang Zhouwei , Kasai Yosuke , Perez Elizabeth , Kim Grace E. , Thirlwell Chrissie , Nakakura Eric , Meyerson Matthew 
Published: June 2022

Background: Small intestinal neuroendocrine tumors (SI-NETs) are the most common neoplasms of the small bowel, accounting for 40% of all small intestinal malignancies. Previous high-throughput sequencing studies have shown that SI-NETs have a low somatic mutation rate. Loss of heterozygosity (LOH) at chromosome 18 is the most frequent genomic alteration identified, occurring in ~60% of tumors, and the only recurrent mutations reported to date are loss-of-function mutations in CDKN1B in ~10% of tumors. Most previous studies have focused on sequencing a single primary tumor from each SI-NET patient, even though up to 50% of the patients are diagnosed with multiple synchronous tumors. Thus, the mechanisms by which multifocal SI-NETs arise remain elusive. A better understanding of their tumorigenesis is essential for the optimal treatment of the patients.

Materials and Methods: We performed a comprehensive genomic profiling of 75 de-identified synchronous primary tumors, 15 metastases, and 18 normal ileal mucosa and/or whole blood specimens from 13 patients with multifocal ileal NETs using whole genome sequencing.

Results: We observed lack of shared somatic variation among the multifocal ileal NET patients and between the synchronous primary tumors within each patient, indicating that these tumors develop independently. Although recurrent copy-number alterations were identified, additional chromosome mapping revealed that tumors from the same patient can gain or lose different parental alleles. In addition to the previously reported CDKN1B loss-of-function mutations, we identified potential driver gene alterations in TNRC6B in a subset of ileal NETs. We also observed two different metastatic dissemination patterns among patients with multiple metastases. Metastases were either clonal or independent, originating from one or several primary tumors.

Conclusions: Our study demonstrates notable genomic diversity among multifocal ileal NETs, which corroborates previous literature suggesting that these tumors originate independently. We identified potential loss-of-function mutations in TNRC6B, a candidate tumor suppressor gene in a small subset of ileal NETs. Identification of different metastatic dissemination patterns has an important clinical implication, highlighting the need to carefully remove all synchronous primary tumors of the entire jejunum and ileum at the time of surgery. Lastly, our results indicate that the tumorigenesis of multifocal ileal NETs is not exclusively driven by genomic alterations, suggesting that SI-NETs could be also driven by epigenetic mechanisms, or arise from morphologically normal small intestine as a result of field cancerization. Also, the tumor microenvironment in the ileum may play a role in the growth and development of SI-NETs.

Citation Format: NETTA MÄKINEN, Meng Zhou, Zhouwei Zhang, Yosuke Kasai, Elizabeth Perez, Grace E. Kim, Chrissie Thirlwell, Eric Nakakura, Matthew Meyerson. Independent clonal origins of synchronous primary tumors in multifocal ileal neuroendocrine tumor patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 46.