Abstract 2744: Familial multiple metastatic small intestine neuroendocrine tumors: searching for genetic susceptibility
Authors: Aavikko Mervi , Kaasinen Eevi , Donner Iikki , Lehti Kaisa , Gucciardo Erika , Shrestha Bideep , Mecklin Jukka-Pekka , Johannes Järnhult , Landerholm Kalle , Pukkala Eero , Schalin-Jäntti Camilla , Ristimäki Ari , Vahteristo Pia , Aaltonen Lauri A. 
Published: August 2015

Small intestinal neuroendocrine tumors (SI-NETs) originating from the enterochromaffin cells of the intestinal mucosa are among the most common tumors in the small intestine. In the past few decades the incidence of SI-NETs has increased more than four-fold in the Western countries. Although SI-NETs are usually well differentiated and indolent with low mitotic activity, multiple discontinuous tumors are present in up to 1/3 of the patients and metastases are found in the majority of the patients at diagnosis.

Previous studies have described significantly elevated risk for gastrointestinal NETs in family members of affected individuals. Our recent nationwide registry-based analyses also showed high familial enrichment for SI-NETs. MEN1 syndrome (MIM#131100) patients are often affected by foregut NETs, but no genetic predisposition factor is known for SI-NETs.

We have studied a Finnish family of five affected individuals with multiple SI-NETs. The affected individuals had also been diagnosed with numerous adenomas of the colon. The family exhibits autosomal dominant inheritance of SI-NETs with affected individuals in two generations. To identify the possible genetic predisposing factor, we performed genome-wide SNP genotyping and linkage analysis followed by exome and genome sequencing. In addition, we have studied the somatic alterations of the tumors by genome-wide copy number analysis and exome sequencing.

We have identified candidate chromosomal regions and genetic variants in this family. Currently we are functionally validating the pathogenicity of the variants and screening the variants in additional familial and sporadic cases with SI-NETs, including a Swedish family of three affected individuals in three generations and Finnish familial and sporadic cases identified through Finnish Cancer Registry. Increased understanding of tumor susceptibility is of great importance in creating tools for better diagnosis and management of the patients. Characterization of novel tumor susceptibility conditions and identification of the associated gene defects also enable studies on gene's biological function and role in other relevant phenotypes or associated tumor types.

Citation Format: Mervi Aavikko, Eevi Kaasinen, Iikki Donner, Kaisa Lehti, Erika Gucciardo, Bideep Shrestha, Jukka-Pekka Mecklin, Järnhult Johannes, Kalle Landerholm, Eero Pukkala, Camilla Schalin-Jäntti, Ari Ristimäki, Pia Vahteristo, Lauri A. Aaltonen. Familial multiple metastatic small intestine neuroendocrine tumors: searching for genetic susceptibility. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2744. doi:10.1158/1538-7445.AM2015-2744