Telomeres, telomerase and colorectal cancer

Table 1 Telomeres and telomerase: outstanding questions regarding their role in the genesis and progression of colorectal cancer

Is the shortening of telomeres an early or late event in colorectal carcinogenesis?

Does telomere shortening play a role in genomic instability?

Do telomere lengths correlate with telomerase expression/activity?

Do telomere lengths correlate with disease progression?

Do levels of telomerase expression/activity increase with disease progression?

Do telomere and/or telomerase act as prognostic markers for disease outcome?

Table 2 Telomere lengths and colorectal cancer

Ref.	Cases	Main findings
Hastie et al[31], 1990	23 (20 CRCs, 3 adenomas) and patient-matched non-cancerous mucosa (frozen samples)	TL
		Decrease with age in non-cancerous cells (33 bp per year)
		Shorter in CRCs and adenomas than in normal mucosa
Engelhardt et al[32], 1997	80 (50 CRCs, 20 polyps, 10 colitis) and CRC patient-matched non-cancerous mucosa (frozen samples)	TL
		Shorter in CRCs than in normal mucosa
		Shorter in CRCs than in polyps and colitis
		Longer in late-stage cancer with higher telomerase activity
		Do not differ between colon and rectum cancer
Takagi et al[33], 1999	61 CRC (including 12 non-ulcerating and 39 ulcerating tumours, according to Borrmann's classification) and patient-matched non-cancerous mucosa (frozen samples)	TL
		Shorter in non-ulcerating CRCs than in normal mucosa
		Shorter in non-ulcerating than in ulcerating tumours
		Not correlated with tumour stage or grade
		Not correlated with telomerase activity
Katayama et al[34], 1999	35 (26 CRCs, 9 polyps) (frozen samples)	TL
		Do not differ between CRCs and polyps
Nakamura et al[35], 2000	124 CRC and patient-matched non-cancerous mucosa (frozen samples)	TL
		Shorter in CRCs than in normal mucosa
		Decrease with age in both cancer and non-cancerous cells (44 and 50 bp/yr)
Plentz et al[36], 2003	10 (adenoma-carcinoma transition) (paraffin-embedded samples)	TL
		Shorter in high-grade dysplastic areas than in the surrounding adenoma
Gertler et al[37], 2004	57 CRC and patient-matched non-cancerous mucosa (frozen samples)	TL
		Shorter in CRCs than in adjacent mucosa
		Decrease with age only in non-cancer cells (19 bp per year)
		Correlate with tumour stage, being longer in advanced tumours
		Correlate with TERT mRNA levels
		Lead to a poor prognosis if TL cancer/TL non-cancer > 0.9
		Do not differ between colon and rectum cancer
Garcia-Aranda et al[38], 2006	91 CRC (23 right-colon, 13 left-colon, 55 rectum) and patient-matched non-cancerous mucosa (frozen samples)	TL
		Shorter in CRC than in adjacent mucosa
		Shorter in right-colon cancers than in tumours located in other sites
		Shorter in poorly differentiated tumours
		Tend to be longer in telomerase-positive CRCs
		Have prognostic value (longer telomeres: poor clinical outcome)
		Correlated with the expression of TRF1 protein
O’Sullivan et al[39], 2006	38 (26 adenomas, 12 CRCs) (paraffin-embedded samples)	TL
		Shorter in adenomas than in adjacent and distant mucosa
		Similar in CRCs and adjacent and distant mucosa
Raynaud et al[40], 2008	15, each case with normal mucosa, low-grade dysplasia, high-grade dysplasia and carcinoma (paraffin-embedded samples)	TL
		Shorter in low-grade and high-grade dysplasia than in carcinoma
		Inversely correlated with activation of the DDR pathway
Rampazzo et al[41], 2010	118 CRC (53 right-colon, 30 left-colon, 35 rectum) and patient-matched non-cancerous mucosa (frozen samples)	TL
		Shorter in CRCs than in adjacent mucosa
		Shorter in right-colon cancers than in tumours located in other sites
		Shorter in MSI than in MSS tumours
		Decrease with age only in non-cancer cells
		Not correlated with tumour stage or grade
		Not correlated with TERT mRNA levels
Valls et al[42], 2011	147 CRC and patient-matched non-cancerous mucosa (frozen samples)	TL
		Shorter in CRCs than in adjacent mucosa
		In cancer correlate with TL in normal mucosa
		Do not differ between colon and rectum cancer
		Not correlated with tumor stage
		Have prognostic value (TL cancer/TL non-cancer ≤ 1: higher OS)
Roger et al[43], 2013	135 (85 polyps from 10 patients with FAP, 50 CRCs) (frozen samples)	TL
		Shorter in polyps than in normal mucosa
		Correlated with genomic rearrangement in polyps
		Independent of adenoma size
		In polyps may reflect the TL of the originating cells

TL: Telomere lengths; CRC: Colorectal cancer; DDR: DNA damage response; OS: Overall survival; FAP: Familial adenomatous polyposis.

Table 3 Telomerase as a marker of disease in colorectal cancer

Ref.	Cases	Main findings
Engelhardt et al[32], 1997	80 (50 CRCs, 20 polyps, 10 colitis) cancerous and 50 CRC patient-matched non-cancerous mucosa specimens	Telomerase activity
		Absent in normal tissues
		Higher in CRCs than in nonneoplastic lesions
		Higher in late-stage than in early-stage tumours
Tatsumoto et al[58], 2000	100 CRC and patient-matched non-cancerous mucosa specimens	Telomerase activity
		Higher in CRC than in adjacent non-cancerous mucosa
		Detectable in adjacent non-cancerous mucosa derived from intestinal crypt basal cells
		Not correlated with CRC stage or grade
		Has prognostic value for OS and DFS (high telomerase activity: poor prognosis)
Niiyama et al[59], 2001	140 CRC and patient-matched non-cancerous mucosa specimens; 20 adenomas	TERT mRNA and telomerase activity
		Higher in CRCs than in adenomas
		Higher in adenomas than in normal mucosa
Naito et al[60], 2001	66 (50 adenomas, 6 mucosal carcinomas, 10 invasive carcinomas) specimens	Positive correlation between TERT mRNA and telomerase activity
		TERT levels increase with adenoma-carcinoma sequence
Gertler et al[61], 2002	57 CRC and patient-matched non-cancerous mucosa specimens	Both CRC and adjacent non-cancerous mucosa are positive for TERT
		TERT levels lower in tumours than in non-cancerous mucosa in most cases
		TERT levels not correlated with tumour stage
		TERT has prognostic value for OD and DFS (high telomerase activity: poor prognosis)
Kawanishi-Tabata et al[62], 2002	122 CRCs, stage II(52 colon, 70 rectum)	80% of CRC are telomerase-positive
		Higher percentage of telomerase-positive tumours in the colon than in the rectum
		High telomerase activity: Good prognosis
Ghori et al[63], 2002	30 CRCs and 20 patient-matched non-cancerous mucosa specimens	Telomerase activity
		Higher in CRCs than in adjacent non-cancerous mucosa
		Correlated with Duke's stage
Boldrini et al[64], 2002	36 CRC and patient-matched non-cancerous mucosa specimens, 8 adenomatous polyps, 9 dysplastic polyps	Telomerase activity
		Absent in normal mucosa and adenomas
		Higher in CRCs than in dysplastic polyps
		Higher in late-stage than in early-stage tumours
Maláska et al[65], 2004	41 CRC and patient-matched non-cancerous mucosa specimens	Telomerase activity
		Present in 83% of CRCs
		Absent or at very low level in normal mucosa
		Higher in metastatic tumours
Boldrini et al[66], 2004	43 CRCs	TERT levels and telomerase activity higher in tumours with mutated TP53
Sanz-Casla et al[67], 2005	103 CRCs	Telomerase activity increases with tumour progression (Duke's stage)
		Higher percentage of telomerase-positive tumours in the colon than in the rectum
		Telomerase activity has prognostic value for DFS (high telomerase activity: poor prognosis)
Garcia-Aranda et al[38], 2006	91 CRC and patient-matched non-cancerous mucosa specimens	Telomerase activity
		Present in 81% of CRCs
		Present at very low levels in 15% of normal samples
		Not correlated with tumour progression
		No prognostic value
Vidaurreta et al[68], 2007	97 CRCs	Telomerase activity
		Present both in MSI and MSS tumours
		Has prognostic value for OS (high telomere activity: poor prognosis)
Bautista et al[69], 2007	108 rectal cancer and patient-matched non-cancerous mucosa specimens	Telomerase activity
		Higher in rectal cancer than in normal mucosa
		Not correlated with tumour stage and grade
		Has prognostic value for DFS and OS
Terrin et al[55], 2008	85 CRC and 42 patient-matched non-cancerous mucosa specimens, 49 plasma samples	TERT levels
		Higher in CRCs than in adjacent non-cancerous mucosa
		Increase with tumour stage and grade
		Not correlated with MSI status
		Not correlated with tumour location
		Plasma TERT levels correlated with tumour TERT levels
Valls Bautista et al[70], 2009	6 cases, each with cancer, polyps and normal mucosa; 8 polyps and normal mucosa	Telomerase activity
		Increases with adenoma-carcinoma sequence
Kojima et al[71], 2011	106 CRC and paired adjacent non-cancerous mucosa specimens	Elongation of the 3’OH of telomere by telomerase may increase Malignant potential of cancer cells
		Telomerase activity has prognostic values for OS (telomeraseactivated without 3'OH shortened telomeres: poor prognosis)
Safont et al[72], 2011	48 CRC and adjacent non-cancerous mucosa specimens and 48 plasma samples	Plasma TERT levels correlated with tumour TERT levels
		Higher circulating TERT levels in stage IV tumours
		No correlation between telomerase expression and prognosis
Bertorelle et al[73], 2013	137 CRCs	TERT levels:
		Increase with tumour stage and grade
		Not correlated with MSI status
		Not correlated with tumour location
		Have prognostic value for OS and for both OS and DFS for stage II patients (high TERT levels: poor prognosis)

CRC: Colorectal cancer; DFS: Disease free survival; OS: Overall survival; TERT: Telomerase reverse transcriptase; MSI: Microsatellite instability.