Patterns of chromosome 18 loss of heterozygosity in multifocal ileal neuroendocrine tumors

Abstract

Ileal neuroendocrine tumors (NETs) represent the most common neoplasm of the small intestine. Although up to 50% of patients with ileal NETs are diagnosed with multifocal disease, the mechanisms by which multifocal ileal NETs arise are not yet understood. In this study, we analyzed genome-wide sequencing data to examine patterns of copy number variation in 40 synchronous primary ileal NETs derived from three patients. Chromosome (chr) 18 loss of heterozygosity (LOH) was the most frequent copy number alteration identified; however, not all primary tumors from the same patient had evidence of this LOH. Our data revealed three distinct patterns of chr18 allelic loss, indicating that primary tumors from the same patient can present different LOH patterns including retention of either parental allele. In conclusion, our results are consistent with the model that multifocal ileal NETs originate independently. In addition, they suggest that there is no specific germline allele on chr18 that is the target of somatic LOH.

Keywords: chromosome 18; copy number variation; high-throughput sequencing; ileal neuroendocrine tumor; loss of heterozygosity.

FIGURE 1

Representative images of multifocal ileal NETs from patient 1. A, Resected segment of ileum, showing multifocal NETs indicated by white arrows. B, Hematoxylin and eosin, and C, Chromogranin A staining of representative primary tumor tissue to confirm its neuroendocrine origin

FIGURE 2

Schematic representation of chr18 LOH patterns occurring in multifocal tumors from three ileal NET patients. Red and blue dots in figure inset represent parental chr18 alleles