Table 1.

Significant tumor-specific subtype-dependent differences in TERT expression or telomere length.

Tumour Type	Subtype	Category	Subtype Characterization 1	Potential Rationale 1
BLCA	Basal Squamous	↑ FL-TERT	High expression of stem-like markers [36]	Cellular potency is positively associated with TERT expression and TA activity [37,38]
	Neuronal	↑ αβγ-TERT	High frequency of RB1 mutations, proliferative cell state, increased expression of neural and neuroendocrine genes. Worst survival outcome [36].	N/A.
BRCA	C1	↓ TERT ↓ TL Ratio	Enriched for one or more positive hormone receptors and improved survival outcome [39].	ER promotes TERT expression by binding to TERT promoter [40]. However, ER expression is inversely correlated with TERT expression [41]. Possible negative feedback control system.
COAD/STAD	CIN	↑ TERT	Chromosomal instability [42].	Aneuploidy is associated with telomere deficiency [43,44,45,46,47,48] but increased TERT expression and TA [49]. Aneuploidy-induced telomere replication stress can be alleviated by TA [50].
	GS	↓ TERT	Genome stability [42].	Aneuploidy is associated with telomere deficiency [43,44,45,46,47,48] but increased TERT expression and TA [49]. Aneuploidy-induced telomere replication stress can be alleviated by TA [50].
HNSC	Basal	↓ FL-TERT ↓ TERT ↓ TL Ratio	Enriched NOTCH1 inactivation, decreased SOX2 expression and HRAS-CASP8 co-mutations [51].	NOTCH1 activation results in increased TERT expression and TA in dental follicle cells [52].
LUAD	C2	↑ FL-TERT	Exclusively PP tumors. Enriched for KRAS mutations and STK11 inactivation [53].	KRAS mutation increases TERT expression, TA and TL in immortalized bronchial epithelial and lung adenocarcinoma cells [54].
LUSC	Primitive	↑ FL-TERT Isoform %	Limited differentiating qualities [55]	N/A
SARC	C1	↓ TERT	Primarily LMS tumors with higher frequency of RB1 mutations and no association between TL and ATRX alterations, unlike UPS and MFS tumors [56].	UPS and MFS employ ALT via ATRX alterations, but LMS potentially does via loss of RB1 [29,57]
	C2	↑ TERT	Primarily DDLPS tumors. Sub-cluster of DDLPS tumors based on somatic copy number alteration found to have worse survival and TERT amplification [56].	TERT expression is gene-dosage dependent [58]. TERT amplification events are rare but is associated with the highest TA [29].
	C4	↑ TERT	Exclusively SS tumors. High FGFR3, miR-183 expression and PDE4A promoter methylation [56].	FGFR3 gain-of-function mutations and TERT promoter mutations significantly co-occur in bladder cancer [59].
TGCT	Embryonal	↑ TERT	NSE tumor subtype that arises from early gonadal stem cells and exhibits gonadal morphology [60].	NSE tumors have increased TERT expression, TL and stemness gene expression [61]. TERT expression and TA decline with TCGT differentiation status [62].
THYM	C1, C3	↑ TERT	Higher lymphocyte content [63].	Normal lymphocytes have endogenous TERT expression [64].

¹ TA = telomerase activity; TL = telomere length; ATRX = α-thalassaemia/mental retardation syndrome X-linked; DAXX = death domain-associated protein; ALT = alternative lengthening of telomeres; RB1 = retinoblastoma protein; ER = estrogen receptor; GI = gastrointestinal; PP = proximal proliferative; LMS = smooth muscle differentiated leiomyosarcoma; UPS = undifferentiated pleomorphic sarcoma; MFS = myxofibrosarcoma; DDLPS = dedifferentiated liposarcoma; SS = synovial sarcoma; SE = seminoma; NSE = non-seminoma. ↑ TERT: increased TERT; ↓ TERT: decrease TERT.