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Testicular Tumor Genomics Provide Clues to Disease Development, Treatment Resistance

NEW YORK (GenomeWeb) – A new genomic study of germ cell tumors (GCTs) occurring in the testes is providing a look at genetic patterns associated with disease development and chemotherapy sensitivity.

Researchers from the Broad Institute, the Dana-Farber Cancer Institute, and elsewhere used a combination of whole-exome sequencing and transcriptome sequencing to assess dozens of tumor samples, including pre-cancerous samples, samples from primary GCTs, and samples from metastatic GCTs that had become chemotherapy resistant. Their results, appearing online today in Nature, point to genomic signatures associated with testicular GCT development and highlight features found in tumors most apt to respond to chemotherapy treatment.

"[W]hile GCTs represent a heterogeneous set of histological subtypes, they share a distinct burden and pattern of reciprocal copy number alterations," Dana-Farber Cancer Institute researchers and co-corresponding authors Eliezer Van Allen and Christopher Sweeney, and their colleagues, wrote. "This observation is consistent with the notion that GCTs emerge, in part, through dysregulation in the mitosis/meiosis switch from arrested gonocytes, since this process may result in abnormal chromosomal segregation and persist during the evolution of GCTs."

The work "gives us insights into germ cell tumor biology that haven't been found to this degree and provide a strong base to explore these very interesting findings further," Sweeney added in a statement.

Treatments for GCTs are usually quite effective, the team noted, with cure rates surpassing 80 percent in individuals with metastatic germ cell tumors. Even so, the disease is typically fatal in roughly one in 10 individuals, sparking ongoing interest in strategies for successfully treating these cases.

The researchers did exome sequencing on 59 formalin-fixed, paraffin-embedded tumor and matched normal samples from 49 individuals treated at the Dana-Farber Cancer Institute or Brigham and Women's Cancer Center from 1997 to 2014. These included 47 individuals with testicular GCTs and two with primary mediastinal GCTs.

The team did not track down one single gene culprit in its search for germ cell tumor drivers, but found that KRAS mutations were over-represented in primary testicular GCTs relative to germ cell neoplasia samples preceding cancer. The results also reaffirmed previously described ties between reciprocal loss of heterozygosity involving a region of chromosome 12 and germ cell tumors, along with a range of relatively dramatic gains and losses.

When they scrutinized these sequences alongside the patients' clinical outcomes, the researchers noted treatment responsive testicular GCTs tended to have wild type versions of the TP53 tumor suppressor gene, as did tumors with mitochondrial priming and other features associated with activation of pro-apoptotic pathways in response to chemotherapy.

Based on a phylogenetic analysis that included sequence data for sequential samples from five individuals with drug resistant tumors, the team saw a further uptick in reciprocal loss of heterozygosity associated with resistance, as well as transcriptional shifts linked to a loss of pluripotency and shifts to more differentiated cell types.

"[C]hemosensitivity in [testicular germ cell tumors] may be the result of high mitochondrial priming properties, and molecular characterization paired with mitochondrial priming studies of treatment-resistant tumors may inform features exclusive to this rare patient subset with significant unmet medical need for new therapies," the authors concluded. "This strategy may also inform strategies to improve the efficacy of chemotherapy in other malignancies."