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Impact of telomere length for risk assessment and prognosis in papillary thyroid cancer depending on the clinicopathological features

Alwehaidah MS, Al-Awadhi R, AlRoomy M, Baqer TA

Mol Genet Genomics, 2024 Dec 20;300(1):2.
PMID: 39704849 DOI: 10.1007/s00438-024-02207-5

OBJECTIVE: . Despite the establishment of a link between telomere status and carcinogenesis, lack of a consensus in the cancer specific pattern of telomere length has a severe impact on the use of relative telomere length (RTL) in cancer diagnosis. The disparity in assessing the relationship between telomere length and cancer risk is complex and may vary as it is influenced by other factors. The objective of this study is to thoroughly examine the intricate relationship between telomere length and cancer incidence in Papillary Thyroid Cancer (PTC) depending on the tumor type, stage, patients' sex and age. Therefore, the current study is focused on the association of RTL in PTC patients with different clinicopathological characteristics and compared with controls to determine the risk of PTC and expected survival time after surgery.
METHOD: . This study included 126 patients with PTC and 80 controls. RTL in thyroid tissues was measured using quantitative (q) PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression analysis. Kaplan-Meier and Cox regression were used to analyze postsurgical outcomes.
RESULT: . The RTL of patients was significantly shorter than that of controls. A short RTL was significantly correlated with an elevated risk of PTC in patients aged ≥ 55 years, female sex, classic subtype, and tumor size > 2 cm. A short RTL did not affect the overall survival of patients with PTC; however, it was associated with poor survival in patients with tumor size > 2 cm and tumor invasion.
CONCLUSION: . This unique study combines the use of RTL with various clinicopathological features of patients with PTC. In conclusion, RTL is a promising tumor marker that correlates with the clinical characteristics of patients with PTC. Specifically, RTL 2 cm and tumor invasion to predict the risk of PTC development and prognosis of the disease. This study will open new horizon in the use of molecular marker such as RTL for understanding its association with increased cancer risk in patients with different clinicopathological features.

Matched MeSH terms: Telomere Homeostasis/genetics
Fulltext Assessment of Telomere Length in Archived Formalin-Fixed, Paraffinized Human Tissue Is Confounded by Chronological Age and Storage Duration

Kong PL, Looi LM, Lau TP, Cheah PL

PLoS One, 2016;11(9):e0161720.
PMID: 27598341 DOI: 10.1371/journal.pone.0161720

Telomeres shorten with physiological aging but undergo substantial restoration during cancer immortalization. Increasingly, cancer studies utilize the archive of formalin-fixed, paraffin-embedded (FFPE) tissues in diagnostic pathology departments. Conceptually, such studies would be confounded by physiological telomere attrition and loss of DNA integrity from prolonged tissue storage. Our study aimed to investigate these two confounding factors. 145 FFPE tissues of surgically-resected, non-diseased appendixes were retrieved from our pathology archive, from years 2008 to 2014. Cases from 2013 to 2014 were categorized by patient chronological age (0-20 years, 21-40 years, 41-60 years, > 60 years). Telomere lengths of age categories were depicted by telomere/chromosome 2 centromere intensity ratio (TCR) revealed by quantitative fluorescence in situ hybridization. Material from individuals aged 0-20 years from years 2013/2014, 2011/2012, 2009/2010, and 2008 were compared for storage effect. Telomere integrity was assessed by telomere fluorescence intensity (TFI). Epithelial TCRs (mean ± SD) for the respective age groups were 4.84 ± 2.08, 3.64 ± 1.21, 2.03 ± 0.37, and 1.93 ± 0.45, whereas corresponding stromal TCRs were 5.16 ± 2.55, 3.84 ± 1.36, 2.49 ± 1.20, and 2.93 ± 1.24. A trend of inverse correlation with age in both epithelial and stromal tissues is supported by r = -0.69, p < 0.001 and r = -0.42, p < 0.001 respectively. Epithelial TFIs (mean ± SD) of years 2013/2014, 2011/2012, 2009/2010 and 2008 were 852.60 ± 432.46, 353.04 ± 127.12, 209.24 ± 55.57 and 429.22 ± 188.75 respectively. Generally, TFIs reduced with storage duration (r = -0.42, p < 0.001). Our findings agree that age-related telomere attrition occurs in normal somatic tissues, and suggest that an age-based reference can be established for telomere studies on FFPE tissues. We also showed that FFPE tissues archived beyond 2 years are suboptimal for telomere analysis.

Matched MeSH terms: Telomere Homeostasis/genetics*
Fulltext Mitochondrial DNA copy number variation, leukocyte telomere length, and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Campa D, Barrdahl M, Santoro A, Severi G, Baglietto L, Omichessan H, et al.

Breast Cancer Res, 2018 04 17;20(1):29.
PMID: 29665866 DOI: 10.1186/s13058-018-0955-5

BACKGROUND: Leukocyte telomere length (LTL) and mitochondrial genome (mtDNA) copy number and deletions have been proposed as risk markers for various cancer types, including breast cancer (BC).
METHODS: To gain a more comprehensive picture on how these markers can modulate BC risk, alone or in conjunction, we performed simultaneous measurements of LTL and mtDNA copy number in up to 570 BC cases and 538 controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. As a first step, we measured LTL and mtDNA copy number in 96 individuals for which a blood sample had been collected twice with an interval of 15 years.
RESULTS: According to the intraclass correlation (ICC), we found very good stability over the time period for both measurements, with ICCs of 0.63 for LTL and 0.60 for mtDNA copy number. In the analysis of the entire study sample, we observed that longer LTL was strongly associated with increased risk of BC (OR 2.71, 95% CI 1.58-4.65, p = 3.07 × 10- 4 for highest vs. lowest quartile; OR 3.20, 95% CI 1.57-6.55, p = 1.41 × 10- 3 as a continuous variable). We did not find any association between mtDNA copy number and BC risk; however, when considering only the functional copies, we observed an increased risk of developing estrogen receptor-positive BC (OR 2.47, 95% CI 1.05-5.80, p = 0.04 for highest vs. lowest quartile).
CONCLUSIONS: We observed a very good correlation between the markers over a period of 15 years. We confirm a role of LTL in BC carcinogenesis and suggest an effect of mtDNA copy number on BC risk.

Matched MeSH terms: Telomere Homeostasis/genetics*
Fulltext Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

Braun DA, Rao J, Mollet G, Schapiro D, Daugeron MC, Tan W, et al.

Nat Genet, 2017 Oct;49(10):1529-1538.
PMID: 28805828 DOI: 10.1038/ng.3933

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

Matched MeSH terms: Telomere Homeostasis/genetics