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.

Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine

“…However, multifocality is common in all SI-NET (Choi et al, 2017; Gangi et al, 2018), and key clinical parameters such as survival or age of diagnosis, which is typically lower for hereditary cancer, are similar in patients with or without multifocality (Choi et al, 2017; Gangi et al, 2018). The observation that the most recurrent somatic genetic event in SI-NET, chr18 loss, can affect both the maternal and the paternal chromosome homologs in the same patient argues against contribution from a predisposing chr18 germline variant by loss of heterozygosity (Zhang et al, 2020). Furthermore, in stark contrast to germline-induced gastrointestinal tumors, SI-NET only affects a limited intestinal segment.…”

“…The evolutionary relationships that govern multiple intestinal tumors and metastases in SI-NET can give insight into the underlying biology, but earlier efforts to determine this have yielded conflicting results (Guo et al, 2000; Katona et al, 2006). A study of copy number alterations (CNA) in multifocal SI-NET primary tumors found that loss of chromosome 18 (chr18), the most frequent CNA, can affect different chromosome homologs in different samples within a patient (Zhang et al, 2020), compatible with an independent clonal origin or late loss of chr18. Alternatively, multifocal SI-NETs have been proposed to represent “drop metastases” originating from regional lymph nodes, consistent with the limited spatial distribution of the intestinal tumors (Wang et al, 2014).…”

Unifocal versus Multiple Ileal Neuroendocrine Tumors Location: An Embryological Origin

“…Further studies are needed to understand whether there are differences in carcinogenesis between unifocal and multiple SI-NET. It has been proposed that multiple SI-NET represent “drop metastases” [20], consistent with the limited spatial distribution of the tumors, but this hypothesis does not match with the independent clonal origin of multiple tumors within a patient [21, 22].…”

Clinical Features, Management, and Molecular Characteristics of Familial Small Bowel Neuroendocrine Tumors

“…Looking at the above studies, one can see that the only common finding is that there is frequently a loss of heterozygosity in chromosome 18 in SBNET, but the specific gene alteration is not consistent across studies. Furthering this point, a recent study investigating multifocal disease in sporadic SBNET patients showed that primary tumors from the same patient could present with different distinct patterns of chromosome 18 allelic loss (24). Additional chromosomal alterations identified in SBNET have included copy number gains in chromosomes 4, 5, 14, and 20 (12,13).…”