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Integrated Analyses Offer New Molecular Insights to Testicular Tumor Subtypes

NEW YORK (GenomeWeb) – An international team led by investigators at the University of North Carolina at Chapel Hill has identified integrated multi-omic features found within and between testicular germ cell tumor (TGCT) subtypes.

The researchers used a combination of exome sequencing, RNA sequencing, microRNA sequencing, and array-based SNP, DNA methylation, and reverse-phase protein profiling to glean genomic, transcriptomic, epigenomics, and proteomic patterns in 137 primary tumor samples from 133 individuals with TGCT. Their analysis revealed three genes with recurrent somatic mutations in one of the four TGCT histological subtypes.

More broadly, the team saw mutation, copy number, methylation, miRNA, and/or immune infiltration combinations that demarcated subsets of tumors within that seminoma subtype, along with molecular markers associated with the three other TGCT subtypes, known as embryonal carcinomas, yolk sac tumors, and teratomas. The study was published online today in Cell Reports.

"Integration of tumor characteristics and genomic and epigenomics data revealed distinctive molecular landscapes of TGCT histologic types, and identified previously unappreciated diversity within seminomas,"senior author Katherine Hoadley, a genetics researcher at the UNC Chapel Hill Lineberger Comprehensive Cancer Center, and her co-authors wrote.

A 2015 study in Nature Communications by researchers at the Institute of Cancer Research and elsewhere led to four genetic loci associated with the risk of developing TGCTs, while papers published in Nature Genetics last year expanded the suite of testicular cancer-associated loci.

TGCT tumors have typically been classified as either seminomas, which are more often indolent, and non-seminomatous, which often affect younger men and may have higher mortality, the team explained. While several features are already used to distinguish between the subtypes of non-seminomatous TGCT, these tumors may exhibit mixed histology. 

To build on prior exome sequencing studies of TGCTs, the researchers assessed exome sequence, RNA sequence, miRNA sequence, methylation profiles, and array-based copy number alteration patterns in 137 tumor samples, alongside matched normal tissue, from 133 cases of TGCT. As expected, the 72 seminomas in this set clustered apart from the non-seminomatous tumors, based on these molecular data.

The team saw relatively limited mutation frequencies across most of the histological subtypes. Just three genes — KIT, KRAS, and NRAS — were significantly mutated in the TGCTs, and those recurrent mutations were limited to the seminoma subtype. Within seminomas, DNA methylation and immune infiltration differences also tended to coincide with the presence or absence of KIT gene mutations, the group reported.

Still other mutation frequency, ploidy, DNA methylation, and/or miRNA expression shifts corresponded with the remaining non-seminomatous subtypes.

In teratoma and yolk sac tumors, for example, the researchers saw enhanced expression of a miRNA called miR-375 that is typically found at low levels in blood samples from healthy individuals. On the other hand, the embyronal carcinomas had higher-than-usual expression of miR-19 and other miRNAs, they noted, and were marked by DNA methylation at non-canonical cytosine sites.

Together, the authors concluded, the new TGCT molecular profiles "afford a more complete view of previously articulated hypotheses, provide additional insights into mechanisms of TGCT tumorigenesis, and identify possible new approaches to the treatment of TGCTs."