Identifying potential tumor drivers through integration of gene expression and DNA copy number in SI-NET (A02)

Introduction: The genetics of small intestine neuroendocrine tumors (SI-NETs) remains poorly
understood. To date, only CDKN1B has been found recurrently mutated, in approximately 9% of cases.
On the contrary, DNA copy number alterations are found in a majority of cases. The most frequent
aberration is heterozygous loss of chromosome 18. In addition, loss of chromosome 11, and gains on
chromosomes 4, 5 and 14 are common. The cellular mechanisms through which these alterations drive
tumor development are unknown.

Aim(s): To identify tumor driver genes affected by copy number alterations in SI-NETs.

Materials and methods: DNA and RNA was extracted from fresh frozen tumor samples. DNA was subjected to whole genome sequencing followed by copy number analysis. RNA was sequenced and gene expression was quantified. Differential expression analyses were performed based on copy number calls.

Results: Eleven cases were found to have loss of chromosome 18, four cases partial loss of chromosome 11, and six cases gain of chromosome 14. 513 genes were differentially expressed between tumors with and without loss of chromosome 18. 78 genes were differentially expressed between tumors with and without loss of chromosome including known tumor suppressor gene ATM located on chromosome 11. 524 genes were differentially expressed in tumors with gain of chromosome 14.

Conclusion: Our analysis identifies genes that are affected by recurrent copy number aberrations in SI-NETs. These genes are candidate driver genes through a gene dosage effect and warrant further investigations using functional assays.

Keywords: si-net, rna-seq, gene dosage, haploinsufficiency, copy number