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Pan Cancer Analysis Maps Tumor Suppressor Gene Inactivation Events

NEW YORK (GenomeWeb) – A pair of investigators at the University of Texas Health Science Center at Houston has documented the types of tumor suppressor gene (TSG) inactivation events that occur across cancer types, from diminished expression of these genes to mutations that dramatically alter the proteins they produce. 

"Our study provides a landscape view of TSG alterations and their potential impact in 30 cancer types," authors Zhongming Zhao and Peilin Jia, biomedical informatics researchers at UTHealth, wrote in a study published online today in Cell Reports.

With genomic data for more than 5,000 tumors from 33 cancer types or subtypes profiled for the Cancer Genome Atlas project, the researchers performed an integrated analysis aimed at uncovering somatic mutations, copy number changes, and transcriptional shifts that led to the inactivation of 1,229 genes — suspected TSGs found through the Tumor Suppressor Gene database and a related computational analysis.

After identifying apparent inactivation mutations based on a two-hit inactivation model, the team considered the transcriptional consequences of this genetic inactivation of TSGs within and across cancer types. In a series of related analyses, they delved into the relationships between TSG inactivation, the pathways involved and predicted functional effects, and cancer types, uncovering clusters of tumors marked by alterations affecting TSGs with similar functional roles.

"We examined the transcriptional footprint in the form of a cis- and trans-effect, global versus local impacts, lineage versus TSG similarities, and downstream pathways and networks," they explained.

In the process, the team tracked down 277 transcriptome-based TSG inactivation-cancer clusters, including several marked by changes to cell cycle regulatory or DNA damage repair genes such as CDKN2A and TP53, along with clusters involving inactivation of TSGs in epigenetic or chromatin remodeling pathways.

"[T]he transcriptomic changes associated with TSG inactivation events were stronger than the cancer lineage difference," the authors reported, "and the same TSGs inactivated in different cancer types tend to cluster together."

The researchers found that many of the TSG inactivation events led to diminished expression of the TSG in question or broader transcriptional shifts related to the inactivation. 

The authors cautioned that their analysis did not account for TSG inactivation stemming from epigenetic events or alterations leading to TSG loss of heterozygosity. In addition, they noted, it "remains a challenge for future work" to more fully characterize the full suite of alterations leading to TSG inactivation or activation.