Abstract
All tumors have in common to reactivate a telomere maintenance mechanism to allow for unlimited proliferation. On the other hand, genetic instability found in some tumors can result from the loss of telomeres. Here, we measured telomere length in colorectal cancers (CRCs) using TRF (Telomere Restriction Fragment) analysis. Telomeric DNA content was also quantified as the ratio of total telomeric (TTAGGG) sequences over that of the invariable Alu sequences. In most of the 125 CRCs analyzed, there was a significant diminution in telomere length compared with that in control healthy tissue. Only 34 tumors exhibited no telomere erosion and, in some cases, a slight telomere lengthening. Telomere length did not correlate with age, gender, tumor stage, tumor localization or stage of tumor differentiation. In addition, while telomere length did not correlate with the presence of a mutation in BRAF (V-raf murine sarcoma viral oncogene homolog B), PIK3CA (phosphatidylinositol 3-kinase catalytic subunit), or MSI status, it was significantly associated with the occurrence of a mutation in KRAS. Interestingly, we found that the shorter the telomeres in healthy tissue of a patient, the larger an increase in telomere length in the tumor. Our study points to the existence of two types of CRCs based on telomere length and reveals that telomere length in healthy tissue might influence telomere maintenance mechanisms in the tumor.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer-related death in Europe [1]
A total of 135 patients suffering from CRC were included in the present study, among which 125 provided enough tumoral DNA for telomere length/telomeric DNA content analyses
A number of studies have shown that telomere length was smaller in colorectal tumors than in adjacent healthy tissues [17,18,19,25,26,27,28,29,30,31,32,33,34,35]
Summary
Colorectal cancer (CRC) is the second leading cause of cancer-related death in Europe [1]. A genetic model of colorectal carcinogenesis that was proposed around 15 years ago remains a paradigm in studies on solid tumor progression [2]. Microsatellite instability (MSI), chromosomal instability (CIN) as well as CpG island methylator phenotype (CIMP) seem to play a major role in these cancers [1,3]. MSI, or instability of microsatellite sequences, is related to defects in the mismatch repair system of DNA (known as MMR system) and these defects, initially associated with Lynch syndrome, generate two distinct types of phenotypes referred to as MSI-high (MSI-H) and MSI-low (MSI-L) [1]. Loss of MLH1 (mutS homolog 1) function, for instance, originally associated with Lynch syndrome, occurs in 15% to 20% of sporadic CRCs. Lynch syndrome is the result of germline mutations in one of the alleles of MMR genes (mainly MSH2 (MutS protein homolog 2) and MLH1 genes). Tumors with CIN account for around 60% of CRC cases [6]
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