by Dr Gautam Ram Choudhary, AIIMS, Jodhpur
Figure 1: Percentage of GCT with pathogenic variants in genes that can be targeted
There is a renewed interest in the genetic testing and its clinical implications in the germ cell tumors (GCTs) with the recent research being spearheaded by the collaborative effort by The Cancer Genome Atlas group. The germline genetics of testicular GCTs have been probed in the realm of development of testicular cancer, biomarkers and for genes that can have actionable potential for the treatment.
Studies on the somatic genomic profiling have pinpointed the gain of the short arm of chromosome 12, often as an isochromosome (i12p), as the hallmark of GCT, which is the most commonly seen copy number alteration.(1) However, single-gene point mutations are uncommon in GCTs and mutations in KRAS/BRAF, KIT, TP53 and NRAS are commonly reported.(2) Also, some studies have reported that enhanced KIT-PI3K-RAS signalling pathway may play a significant role in the development of most of the seminomas.(3) However, despite the high rates of bilateral and familial cases which are observed in testicular GCT, as of now, a major high-penetrance susceptibility gene has not been identified and the data suggests that a complex polygenic model with considerable variation may play a role in the development of inherited testicular GCT.(2)
In the realm of biomarkers, the role of several micro-RNAs have been explored. Micro-RNA, miRNAs, are short non-coding segments of RNA that alter gene expression by epigenetic modification. Recent studies have evaluated the role of miRNA-371a-3p in the diagnosis and monitoring of the patients with testicular GCTs.(3) For the detection of primary testicular GCT, the miRNA-371a-3p showed a sensitivity of 90%, specificity of 97% and an accuracy of 96% in a cohort of 616 men.(3) Besides the initial diagnosis, the miRNA-371a-3p was found to be associated with clinical stage, primary tumor size and the response to the treatment and was found to outperform the traditional serum tumor markers and was expressed in all histologic subtypes except teratoma.
In the realm of management of GCTs, recent reports have focussed on the actionable genes and tried to identify pathogenic and likely pathogenic genes that can be targeted. The authors of a recent study found that only 11% of the patients had pathogenic or likely pathogenic variants and only 2% of the total population had alteration in the high penetrance genes that could be targeted such as BRCA1/2 and TP53.(4) Besides, recent studies evaluating the role of immune check point inhibitors have not shown promising results, in view of the low tumor mutational burden and low degree of microsatellite instability found in the GCTs. However, a couple of mutations have been identified that can predict the response to the conventional chemothearpy. Tumors with alterations in TP53, amplification of MDM2, loss of expression of pluripotency markers and apoptosis regulators and reciprocal loss of heterogenity are usually resistant to cisplatin based chemotherapy.(2)
To conclude, the most promising recent development in genetic evaluation is the identification of miRNA-371a-3p as the biomarker of GCT and has the potential to replace the traditional serum markers.