Genomic instability is associated with lack of telomerase activation in ovarian cancer.
BACKGROUND
Malignant cells are capable of an unlimited number of cell divisions, either through production of telomerase, or through the alternate lengthening of telomere (ALT) mechanism. Yeast cells with genomic instability have been shown to survive in the absence of telomerase by increased recombination events. We hypothesized that ovarian cancers with high microsatellite instability (MSI-H) are more likely to lack telomerase activation.


METHODS
We examined 104 invasive ovarian cancers for MSI with six microsatellite markers (BAT25, BAT26, D5S346, D2S123, D17S250 and NME1). Telomerase activity was determined with ELISA, and its subunits human telomerase reverse transcriptase (hTERT) and human telomerase RNA (hTR) by RT-PCR. Statistical analysis was performed with Chi-square and p<0.05 was considered significant.


RESULTS
Telomerase activity was detected in 79 samples (76%). The hTERT subunit was detected in 85% of samples, and hTR was found in all ovarian cancers. Presence of hTERT was positively associated with telomerase activity (p=0.001). High MSI (MSI-H), defined as two or more positive markers, was detected in 15% of ovarian cancers; low MSI (MSI-L), defined as having only one positive marker, was found in 13%; the remaining 72% were microsatellite stable (MSI-S). Telomerase activity was detected in 83% of MSI-S and 79% of MSI-L tumors, but only 40% of MSI-H tumors (p=0.002). Interestingly, hTERT was similar in all three groups (range 73-84%, p=0.59), demonstrating that the presence of hTERT transcript was not the only determinant of telomerase activity in MSI-H tumors.


CONCLUSIONS
Ovarian cancers with high MSI are more likely to propagate without the need to produce telomerase.
Landen
Charles N
CN
Department of Gynecologic Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Klingelhutz
Al
A
Coffin
Jeremy E
JE
Sorosky
Joel I
JI
Sood
Anil K
AK
D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D042822:Genomic Instability; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D010051:Ovarian Neoplasms / Q000201:enzymology*; D012313:RNA / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000378:metabolism*
D004268:DNA-Binding Proteins; D012334:RNA, Neoplasm; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase