Table 1.

Epigenetic-based biomarkers in testicular germ cell tumors in adult and pediatric patients.

Adult		Pediatric
Biomarker	Major Findings	Biomarker	Major Findings
DNA Methylation
VGF, MGMT, ADAMTS1,CALCA, HOXA9, CDKN2B, CDO1, and NANOG	Hypermethylation of MGMT and CALCA promoters associateswith non-seminoma and poor prognosis CALCA associates with refractory disease. [69]	RUNX3	RUNX3 promoter hypermethylation was detected in YST in infants (80%). [74]
MGMT, RASSF1A, BRCA1, and a transcriptional repressor gene HIC1	Non-seminoma showed methylation in MGMT, RASSF1A, and BRCA1 and HIC1. Seminoma showed a near-absence of methylation. [70]	APC	APC promoter hypermethylation was detected in YST in infants (70%). [75]
RASSF1A, HIC1, MGMT, and RARB	Hypermethylation of RASSF1A and HIC1 was associated with tumors resistant to cisplatin-based regimens, whereas MGMT and RARB were sensitive. [71]	Epigenome-wide study	DMRs were identified in a set of 154 pediatric tumors from gonadal, extragonadal and intracranial locations. [77]
XIST	Unmethylated DNA XIST fragments in seminoma and non-seminoma. [73]
CRIPTO	Hypomethylation in undifferentiated fetal germ cells, embryonal carcinoma and seminomas. Hypermethylation in differentiated fetal germ cells and the differentiated types of non-seminomas. [72]
LINE-1	Strong correlation in LINE-1 methylation levels among affected father-affected son pairs. LINE-1 hypomethylation was associated with the risk of testicular cancer. [76]
Genetic abnormalities
Isochromosome 12p	The most commonly observed change in all histological subtypes of TGCTs. [8,34,35]	Isochromosome 12p	Less frequent in types I and II. [40,41,42].
Chr 7, 8, 21, 22, and X	Gains at the arm level target. [38,39]	Chr 1, 3, 11, 20, and 22	Gains in 1q, 3, 11q, 20q, and 22 are common, but still inconsistent. [9,43]
RAS family (HRAS, KRAS, and NRAS)	More common in seminoma when compared to non-seminoma [36,60,61].
TP53	Rarely described in GCTs but, when present, they were associated with a cisplatin-resistant disease, especially in patients with non-seminoma mediastinal [47,48,49,50].
FGFR3, AKT1, PIK3CA	Associated with cisplatin-resistant GCTs [54].
TERT	TERT promoter mutation is rare [64].
KIT and KRAS	KIT mutations in GCTs are associated with RAS/MAPK pathway driver alterations [57].
BRAF	BRAF mutation was absent [62,63,87,88].
microRNA
miR-372 and miR-373	miR-372 and miR-373 were particularly abundant in GCT tissue and cell lines. [82]	miR-371~373 and miR-302 clusters	miR-371~373 and miR-302 clusters were overexpressed regardless of histological subtype, site (gonadal/extragonadal), or patient age (pediatric/adult) [83].
miR-371~373 and miR-302/367	miR-371~373 and miR-302/367 as biomarkers of malignant GCTs were reported [84].
miR-371a-3p	Serum miR-371a-3p levels provide both a sensitivity and a specificity greater than 90% and an area under the curve (AUC) of 0.96 [20]. The miR-371a-3p test showed a specificity of 100%, sensitivity of 93%, and AUC of 0.978 [85].