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Genomics in the Journals: Mar 27, 2014

NEW YORK (GenomeWeb News) – A trio of papers in Nature Genetics describe findings from genomic studies of an ovarian cancer called small cell carcinoma of the ovary, hypercalcemic type, that implicate mutations in the SMARCA4 gene in the development of the disease.

In the first paper, researchers hailing from Translational Genomics Research Institute, the University of British Columbia, and elsewhere described performing whole-genome and -exome sequencing of 12 cases, including tumor and germline samples, and on a SCCOHT cell line. From this, they noted that the only recurrent mutation in those samples was in the chromatin-remodeling gene SMARCA4.

They further found that the SMARCA4 protein was lost in some 82 percent of SCCOHT cases as compared to 0.4 percent of other primary ovarian cases.

Similarly, McGill University's William Foulkes and colleagues also reported uncovering SMARCA4 mutations in three families with a history of SCCOHT by sequencing the exomes of afflicted family members. They then also found SMARCA4 mutations in affected members of a fourth family.

The McGill group also found, using immunohistochemical analysis, that the SMARCA4 protein was lost in 38 of the 40 tumors they analyzed, from both familial and non-familial cases.

The third study, from Memorial Sloan-Kettering Cancer Center researchers, likewise implicated SMARCA4 in SCCOHT. All 12 of the tumor samples they sequenced as part of their tumor-normal sequencing study harbored biallelic SMARCA4 mutations. Additionally, their immunohistochemistry analysis showed SMARCA4 protein loss in the tumor samples.

This, all three sets of researchers said, suggests a role for the SWI/SNF chromatin remodeling complex in SCCOHT development.

"The loss of normal SWI/SNF complex function might therefore represent a key tumorigenic step in SCCOHT and might further constitute a key therapeutic vulnerability in SMARCA4-deficient cells," the TGen-led team wrote.

Indeed, the Sloan-Kettering-led researchers suggested that inhibitors of the highly similar SMARCA2 ATPase could be a possible treatment for such deficient tumors.

Further, as SCCOHT can be difficult to diagnose pathologically, since it is morphologically similar to other cancers, both the TGen and McGill teams said that the loss of the SMARCA4 protein could be used as a marker to indicate SCCOHT.

"Many genetic anomalies can be like a one-lane road to cancer — difficult to negotiate," said Jeffrey Trent, the president and research director of TGen, and senior author of the first study. "But these findings indicate a genetic superhighway that leads right to this highly aggressive disease."


In PLOS One, the Woods Hole Oceanographic Institution's Tracy Mincer and colleagues described a relatively simple core community of microorganisms that's found on the skin of humpback whales from distinct populations in the North Atlantic, North Pacific, and South Pacific ocean regions. The team used Roche 454 sequencing to identify members of whale skin microbiomes based on bacterial small-subunit ribosomal RNA-coding sequences.

From skin samples that had been biopsied or sloughed off of 56 humpback whales, the researchers found that some aspects of the animals' skin microbiomes differed depending on their geographic locale, feeding status during migration and breeding seasons, and so on.

But other features remained relatively stable. For instance, the study's authors saw that healthy humpback whales typically carried microbial species from the Tenacibaculum and Psychrobacter genera in their skin communities. In contrast, those microbes and other members of the core skin microbiome were often found at lower-than-usual levels in whales that were stressed or unhealthy.

"It is astonishing that we find Tenacibaculum and Psychrobacter [species] bacteria on whale skin regardless of animal age, sex, metabolic state, geographic region or population," first author Amy Apprill, with the Woods Hole Oceanographic Institution, said in a statement.

"These bacteria may be involved in an important interaction with the whales," she noted. "With further development, we might be able to gain insight into the health of whales by examining their skin bacteria."


FANTOM5 project researchers published a suite of papers this week, including two in Nature describing their development of a transcription start site map and their identification of enhancer candidates.

“Humans are complex multicellular organisms composed of at least 400 distinct cell types. This beautiful diversity of cell types allow us to see, think, hear, move and fight infection yet all of this is encoded in the same genome," RIKEN's Alistair Forrest, scientific coordinator of FANTOM5, said in a statement.

"The difference between all these cells is what parts of the genome they use – for instance, brain cells use different genes than liver cells, and therefore they work very differently," Forrest added. "In FANTOM5, we have for the first time systematically investigated exactly what genes are used in virtually all cell types across the human body, and the regions which determine where the genes are read from the genome."

In one of the Nature papers, the FANTOM5 project researchers describe using single-molecule sequencing to perform cap analysis of gene expression (CAGE) on some 975 human and 399 mouse samples, including primary cells, tissue, and cancer cell line samples. They then mapped transcription start sites and their usage in those cell types.

From this, the researchers noted that there are very few truly 'housekeeping' genes, TSSs that are cell-type specific evolve at different rates that other sites, and promoters of widely expressed genes are highly conserved.

They added that this map is more complete than previous iterations as they have identified and quantified at least one promoter for 95 percent of the annotated protein-coding genes in the human reference genome.

The second paper, meanwhile, used the CAGE-derived expression atlas to identify and describe the activity of more than 43,000 enhancer candidates in various human cell types and tissues. This catalog, the researchers said, will allow the classification of common and cell-type specific enhancers, modeling interactions between enhancers, and more.

They noted that enhancers' bidirectional capped RNAs act as good predictors of enhancer activity, and that they only measure transcription at a portion of chromatin-defined enhancers. This, they added, suggests that chromatin-defined enhancers are not active regulators in that particular cell or cell state, and may be active in other cells or are poised to become active regulators after stimulation.

"The collection of active enhancers presented here provides a resource that complements the activity of the ENCODE consortium across a much greater diversity of tissues and cellular states," the researchers wrote. "It has clear applications in human genetics, to narrow the search windows for functional association, and for the definition of regulatory networks that underpin the processes of cellular differentiation and organogenesis in human development."

The researchers also developed a FANTOM5 online resource, which may be found here.

The Scan

Drug Response Variants May Be Distinct in Somatic, Germline Samples

Based on variants from across 21 drug response genes, researchers in The Pharmacogenomics Journal suspect that tumor-only DNA sequences may miss drug response clues found in the germline.

Breast Cancer Risk Gene Candidates Found by Multi-Ancestry Low-Frequency Variant Analysis

Researchers narrowed in on new and known risk gene candidates with variant profiles for almost 83,500 individuals with breast cancer and 59,199 unaffected controls in Genome Medicine.

Health-Related Quality of Life Gets Boost After Microbiome-Based Treatment for Recurrent C. Diff

A secondary analysis of Phase 3 clinical trial data in JAMA Network Open suggests an investigational oral microbiome-based drug may lead to enhanced quality of life measures.

Study Follows Consequences of Early Confirmatory Trials for Accelerated Approval Indications

Time to traditional approval or withdrawal was shorter when confirmatory trials started prior to accelerated approval, though overall regulatory outcomes remained similar, a JAMA study finds.