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June 13, 2018

Testicular Cancer Mapped Genomically and Epigenomically

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    Seminoma, a common germ cell tumor. [Nephron - Own work, CC BY-SA 3.0, Link

    Testicular germ cell tumors (TGCTs) are one of the most common type of cancer in young men of European descent and are considered to be among the most curable. Researchers for The Cancer Genome Atlas (TCGA) Research Network now report on the results of a comprehensive genetic and epigenetic analysis of 137 TGCTs, which has identified molecular features of the different types of TGCT. They suggest the findings could help to stratify patients and so improve treatment decision making, aid patient monitoring, and offer up new potential therapeutic targets.  

    "We now have a better understanding of the molecular characteristics of the histological subtypes of testicular germ cell cancers," says UNC Lineberger's Katherine Hoadley, Ph.D., assistant professor in the UNC School of Medicine Department of Genetics, and corresponding author of the team’s report, entitled “Integrated Molecular Characterization of Testicular Germ Cell Tumors,” which is published in Cell Reports. She adds, "There is a strong epigenetic component to testicular cancer tumorigenesis."

    There are about 9310 new cases of testicular cancer and 400 related deaths annually in the U.S. However, while the disease is rare and considered to be among the most curable of solid tumors—with 95% of patients surviving for five years—more research is needed to help stratify patients according to risk, and so help to avoid overtreatment and also monitor patients after treatment. “…survivors can experience devastating late effects of treatment, and a pressing research goal is the discovery of rational means of risk stratification that could spare some patients unnecessary chemotherapy, radiation, and surgery,” the authors write.

    There are two major histological types of TGCT, pure classic seminoma and nonseminomatous germ cell tumors (NSGCTs), the reserchers explain. NSGCTs comprise embryonal carcinoma (EC), choriocarcinoma, yolk sac tumor, and teratoma, which can contain a mix of both seminomatous and nonseminomatous components. The researchers characterized 137 TGCTs using multiple genetic and epigenetic analysis techniques, including using DNA exome sequencing, RNA and microRNA (miRNA) sequencing, DNA single-nucleotide polymorphism (SNP) arrays, DNA methylation arrays, and reverse-phase protein arrays.

    Their analyses identified a “paucity” of somatic mutations, but striking differences in global miRNA expression between the histological subtypes, and “dramatically different global DNA methylation patterns.”  

    Somatic mutations in just three genes, KIT (which is involved in development of the testis), KRAS, and NRAS, were found to be of any significance, and only in samples with seminoma components. “Because KIT mutation was never observed in tumors lacking seminoma components, we postulate that this subset of seminomas is locked in a PGC-like [primordial germ cell-like] status and remain pure seminomas, while those lacking KIT mutations may have the potential to differentiate into other histologies,” the team writes. In contrast, aneuploidy was almost universal. “All TGCTs had ploidy exceeding two, but NSGCTs demonstrated significantly lower ploidy than seminomas with variability across histology types.”

    ECs exhibited extensive methylation at noncanonical cytosine sites, whereas global methylation was low in seminomas and was absent in seminomas with KIT/KRAS mutations, “suggesting an essentially complete lack of DNA methylation in this subset.” Interestingly, epigenetic silencing of key tumor suppressors, including BRCA1, MGMT, and RASSF1A, occurred exclusively in NSGCTs. “BRCA1 and RAD51C both are involved in the homologous recombination (HR) DNA repair pathway,” the researchers comment. “Epigenetic silencing of RAD51C has been described in ovarian cancer with BRCA1 deficiency but not in TGCTs.”

    There were differing profiles of miRNA, mRNA, and protein between seminomas and NSGCTs, and a number of miRNAs identified could potentially be used to monitor patients for disease recurrence. The authors suggest that while serum tumor markers are currently used to stratify risk for testicular germ cell tumors, the new results have highlighted additional potential markers that could help to make stratification even more accurate. "We found microRNAS that could be used to detect the different types of testicular cancer, and this potentially could be developed into a minimally invasive serum blood test to determine if their cancer has come back," Dr. Hoadley suggests. "We think that could be important for future screening." EC tumors in particular displayed high expression of multiple miRNAs, the team notes.

    Overall, the KIT-mutated seminomas exhibited “unique characteristics,” which included the highest levels of lymphocyte infiltration, the absence of global DNA methylation, and reduced KRAS mutation frequency and copy number alterations. All of the subtypes of NSCTs shared genomic characteristics, including lower ploidy and higher purity than seminoma. “Recurrent somatic mutations were rarely present in NSGCTs, even though the overall mutation density was not dramatically different from seminomas,” the team writes.

    “Integration of tumor characteristics and genomic and epigenomic data revealed distinctive molecular landscapes of TGCT histologic types and identified previously unappreciated diversity within seminomas,” they conclude. The findings could feasibly lead to new treatment strategies for testicular cancer that target the epigenome, or that increase immune response to tumors. “Treatment-refractory TGCT is rare and mortality is now low, but late effects of chemotherapy and morbidity associated with surgery remain a clinical challenge that several of our results may help to address." 

    "Advanced germ cell tumor treatment remains a success story in the field of oncology, however continued research aimed at increasing cure rates in patient with intermediate and poor-risk disease, and decreasing treatment-related morbidity are desperately needed," comments UNC Lineberger's Matthew Milowsky, M.D., co-director of the UNC Lineberger Urologic Oncology Program and professor in the UNC School of Medicine Division of Hematology/Oncology. “Risk stratification, currently based on clinical factors and serum tumor markers, is critically important in a disease with issues related to both under- and overtreatment. The great majority of patients with good-risk, advanced testicular germ cell tumors are cured; however, both early and late treatment-related complications remain problematic."

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