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Integrated Genomic Studies Offer Clues to Small-Cell Lung Cancer

NEW YORK (GenomeWeb News) – Although an aggressive form of lung cancer known as small-cell lung cancer is marked by high mutation rates, it's still possible to detect recurrent alterations affecting a few main pathways and processes in these cancers by bringing together different types of genomic data, two new studies in Nature Genetics reveal.

Together, the studies interrogated the coding sequences of 63 small-cell lung cancer tumors and 19 tumor-derived cell lines, uncovering some of the same recurrent mutations to histone- and chromatin-modifying genes, along with a few genetic glitches that were distinct to each set of samples.

The new findings are providing the type of genetic details that researchers hope will pave the way for more targeted treatments for small-cell lung cancer, which tends to occur in heavy smokers and often metastasizes quickly.

Less aggressive non-small cell lung cancers such as lung adenocarcinoma and squamous cell lung carcinoma have been genetically characterized in far more detail, authors of the new studies noted, in part because patients with those forms of the disease are more likely to undergo resection surgery, providing a more ready source of tumor samples.

In one of the new studies, a large international team led by investigators at the University of Cologne used Agilent's SureSelect Human All Exon enrichment kit and Illumina GAIIx sequencing to sequence the exomes of 27 small-cell lung cancer tumor samples and two cell lines obtained through a global lung cancer research consortium repository.

The researches also did transcriptome sequencing and array-based SNP analyses on 15 and 63 tumor samples, respectively. Two tumor samples were assessed by whole-genome sequencing on the Illumina HiSeq 2000 to take a look at genomic rearrangements in the cancers.

Because the mutation rate was so high for the small-cell lung tumors, the group brought each of its available data types together to focus on the genetic alterations that were expected to be most probably pathogenic.

That analysis uncovered recurrent mutations in at least three histone-modifying genes, CREBBP, EP300, and MLL, along with mutations in known cancer players such as TP53, RB1, and PTEN. Regions in and around TP53 and RB1 were also frequently missing in the tumors, while recurrent gains were detected for a chromosome 3 region housing the SOX2 gene, the researchers reported. Other fairly frequent changes included amplifications affecting components of the MYC pathway, the FGFR gene, and the CCNE1 gene.

From these results — coupled with follow-up experiments in mice, analyses of later stage human tumors obtained at autopsy, and functional studies on two of the histone-modification proteins identified by exome sequencing — authors argued that integrated analyses of small-cell lung cancers could yield the sorts of genetic insights needed to more effectively tackle the difficult-to-treat disease.

"Our study implicated histone modification as a major feature of [small-cell lung cancer], reveals potentially tractable genomic alterations, and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background," University of Cologne research Roman Thomas, the study's senior author, and his colleagues wrote.

For another study, researchers from Johns Hopkins University, Genentech, and elsewhere used dozens more tumor and cell line samples to explore the genetic basis of small-cell lung cancer by exome, transcriptome, and whole-genome sequencing.

That team initially saw nearly 8,000 protein-changing somatic mutations in the cancers when it used the Illumina HiSeq 2000 to sequence SureSelect-captured coding sequences from 42 small-cell lung cancers and matched normal samples, as well as exome sequences from several other tumor and cell line samples that were missing matched normal samples.

By folding in transcriptome sequence data for 55 small-cell lung tumors or cell lines, along with array-based copy number data on 56 samples, and whole-genome sequence information for one tumor, the researchers narrowed in on 22 genes that were mutated with significant regularity.

As in the German-led study, researchers found recurrent copy number changes affecting SOX2, with more than one-quarter of the tumor and cell line samples tested in the study involved SOX2 amplifications. Their analysis uncovered frequent mutations involving other genes in the SOX family as well.

Amongst the other genes that commonly mutated in the second study were kinase enzyme-coding genes, as well as genes believed to contribute to pathways related to chromatin modification, G-protein receptor function, PI3-kinase signaling, and DNA repair. Several kinase genes turned up as part of fusion transcripts, too, prompting that team to suggest that delving into the function of these fusions could provide an avenue for understanding and possibly treating some small-cell lung tumors.

"Understanding the role of tumor-specific, in-frame kinase fusion transcripts identified in [small-cell lung cancer] in this study may provide promising opportunities for targeted therapy development," senior author Somasekar Seshagiri, a molecular biology researcher at Genentech, and his colleagues noted.

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