Whole Exome Sequencing of Small Intestine Neuroendocrine Tumors May Lead to Development of Personalized Treatment

Whole exome sequencing of small intestine neuroendocrine tumors, the most common malignancy of the small bowel, revealed genomic alterations that might be susceptible to chemotherapy in 72% of the patients studied.

The exome is the part of the genome formed by exons, nucleotide sequences encoded by a gene that remain present within the final mature RNA product of that gene after introns have been removed by RNA splicing. The term exon refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts. The exome of the human genome consists of roughly 180,000 exons constituting about 1% of the total genome, or about 30 megabases of DNA. Though comprising a very small fraction of the genome, mutations in the exome are thought to harbor 85% of disease-causing mutations.


Investigators at the Mayo Clinic (Rochester, MN, USA) analyzed the exomes of small intestine neuroendocrine tumors from 48 patients, along with normal tissue from those same 48 patients. They employed massively parallel, or “nextgen,” DNA sequencing, which facilitates the collection of comprehensive, genome-wide, unbiased datasets providing a common data framework for comparing results across different tumor types and gene sets. This technique provides the most comprehensive technology to date to explore the potential of genomics for individualizing cancer treatment within a tumor type.

Data obtained from analysis of the 96 whole exome sequences was published in the May 15, 2013, online edition of the Journal of Clinical Investigation. The findings revealed that small intestine neuroendocrine tumors samples carried low numbers of point mutations and characteristic recurrent patterns of gene duplications and losses. Candidate therapeutically relevant alterations were found in 35 of the 48 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of the serine-threonine protein kinases AKT1 or AKT2 was the most common event in 16 patients who displayed alterations of PI3K/AKT/mTOR signaling. AKT1 (v-akt murine thymoma viral oncogene homolog 1) is a component of the PI3K/AKT/mTOR pathway, and mutations in AKT1 have been implicated in breast, colorectal, and lung cancers,

“This is a very important step in achieving targeted therapies and individualized treatment approaches for patients with small bowel carcinoids,” said first author Dr. Michaela Banck, an oncologist at the Mayo Clinic. “Genomic analysis of the individual patient’s tumors will help us identify new drugs that are targeted to the individual’s disease.”

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