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Researchers Report on Mutational Patterns in Adenoid Cystic Carcinoma

NEW YORK (GenomeWeb News) – A Memorial Sloan-Kettering Cancer Center-led team has taken an exome- and genome-sequencing centered look at the mutations that may be found in the salivary gland cancer adenoid cystic carcinoma, or ACC.

As they reported in Nature Genetics online yesterday, the researchers did exome or genome sequencing on five-dozen matched ACC tumor and normal pairs.

Their analysis unearthed relatively few glitches in each tumor's protein-coding sequences. But the group found suspicious mutations to several main pathways, including some — such as the PI3-kinase, fibroblast growth factor, and insulin-like growth factor-containing pathway — that may make promising treatment targets.

"Our discovery of genomic alterations in targetable pathways suggests potential avenues for novel treatments to address a typically chemoresistant malignancy," corresponding author Timothy Chan, an oncology researcher at Memorial Sloan-Kettering, and his colleagues wrote, noting that "[v]erified ACC cell lines are needed to further substantiate the clinical usefulness of the mutations identified here."

A few genetic glitches have been linked to ACC in the past, the team noted, including a fusion between the transcription factor genes MYB and NFIB. The tumors are also notorious for having higher-than-usual expression of certain genes, such as the epidermal growth factors. Even so, there is still a ways to go in characterizing and treating the aggressive cancer.

To get a better sense of the nature and frequency of mutations involved in ACC, the researchers used Illumina's HiSeq2000 to do exome sequencing on 55 matched ACC and normal samples, as well as whole-genome sequencing on five more tumor-normal pairs.

For the exome sequencing experiments, they used Agilent SureSelect kits to capture protein-coding portions of the genome prior to sequencing. In the subsequent analyses, meanwhile, the group relied on Life Tehnologies' SOLiD and Illumina's MiSeq platforms to verify apparent single nucleotide glitches and small insertions and deletions.

With 106-fold coverage of the exomes, on average, and 37-fold average coverage of the genomes, the group was able to track down a mean of almost two-dozen somatic coding alterations per tumor.

When they used an algorithm called CHASM to distinguish between driver and passenger mutations in a set of 710 validated non-synonymous mutations, the researchers saw an over-representation of apparent driver mutations affecting genes known for processes ranging from chromatin regulation and DNA damage response to signaling and metabolism.

For instance, more than one-third of the tumors harbored mutations to chromatin regulators or chromatin state modifying genes such as SMARCA2, CREBBP, and KDM6A. Similarly, the researchers tracked down multiple mutations to genes coding for enzymes involved in adding or removing methylation and acetylation marks to histones.

Glitches to DNA damage response pathways also turned up in multiple tumors, they reported, as did mutations involving genes from the FGF-IGF-PI3K and other signaling pathways.

Some 57 percent of the tumors tested contained the MYB-NFIB fusion that had been implicated in ACC previously. But the new analysis also turned up mutations affecting genes that interact with MYB and in the NFIB gene itself, pointing to widespread — and perhaps complex — involvement for the two transcription factors in ACC.

"Our data highlight MYB as an active oncogenic partner in fusion transcripts in ACC," the study's authors said, "but also suggest a separate role for NFIB, given the presence of mutations specific to this gene."

Going forward, the group hopes to see further analyses on alterations uncovered in the current study, particularly those falling in pathways that might be prone to clinical interventions.

"[O]ur data provide insights into the genetic framework underlying ACC oncogenesis," the researchers concluded, "and establish a foundation for identifying new therapeutic strategies."

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