Hi-res telomere FISH reveals intriguing anomalies in germ cell tumors

T esticular G erm C ell T umor (TGCT) is the most common malignancy of young men. Most patients are completely cured which distinguishes these from most other malignancies. Orchiectomy specimens (N = 76) were evaluated using High Resolution (single-cell discriminative) telomere-specific F luorescent I n S itu H ybridization (FISH) with simultaneous Oct4 immunofluorescence to describe telomere length phenotype in TGCT neoplastic cells. For the first time, the TGCT precursor lesion, g erm c ell n eoplasia i n s itu (GCNIS) is also evaluated in depth. The intensity of the signals from cancerous cells was compared to the same patient's reference cells—namely, healthy germ cells (defined as ‘medium’ length) and interstitial/somatic cells (defined as ‘short’ telomere length). We observed short telomeres in the majority of GCNIS and pure seminomas (P = .006 and P = .0005, respectively). In contrast, non-seminomas displayed longer telomeres. Lesion-specific telomere lengths were documented in mixed tumor cases. E mbryonal c arcinoma (EC) demonstrated the longest telomeres. A fraction of EC displays the telomerase-independent a lternative l engthening of t elomeres (ALT) phenotype (24% of cases). Loss of ATRX or DAXX nuclear expression is strongly associated with ALT, however, nuclear expression of both proteins was retained in half of ALT positive EC. The particular distribution of telomere lengths among TGCT and GCNIS precursor implicate telomere anomalies in pathogenesis. These results may advise management decisions as well.