From Journal of Medical Genetics

Shorter Telomere Length Is Associated With Increased Ovarian Cancer Risk in Both Familial and Sporadic Cases

Beatriz Martinez-Delgado; Kira Yanowsky; Lucia Inglada-Perez; Miguel de la Hoya; Trinidad Caldes; Ana Vega; Ana Blanco; Teresa Martin; Rogelio Gonzalez-Sarmiento; Maria Blasco; Mercedes Robledo; Miguel Urioste; Honglin Song; Paul Pharoah; Javier Benitez

Authors and Disclosures

Print This

Abstract and Introduction
Methods
Results
Discussion

References

Abstract and Introduction

Abstract

Background Alterations in telomere maintenance mechanisms leading to short telomeres underlie different genetic disorders of ageing and cancer predisposition syndromes. It is known that short telomeres and subsequent genomic instability contribute to malignant transformation, and it is therefore likely that people with shorter telomeres are at higher risk for different types of cancer. Recently, the authors demonstrated that the genes BRCA1 and BRCA2 are modifiers of telomere length (TL) in familial breast cancer. The present study analysed TL in peripheral blood leucocytes of hereditary and sporadic ovarian cancer cases, as well as in female controls, to evaluate whether TL contributes to ovarian cancer risk.
Methods TL was measured by quantitative PCR in 178 sporadic and 168 hereditary ovarian cases (46 BRCA1, 12 BRCA2, and 110 BRCAX) and compared to TL in 267 controls.
Results Both sporadic and hereditary cases showed significantly shorter age adjusted TLs than controls. Unconditional logistic regression analysis revealed an association between TL and ovarian cancer risk with a significant interaction with age (p<0.001). Risk was higher in younger women and progressively decreased with age, with the highest OR observed in women under 30 years of age (OR 1.56, 95% CI 1.34 to 1.81; p=1.0×10⁻¹⁸).
Conclusion These findings indicate that TL could be a risk factor for early onset ovarian cancer.

Introduction

Telomeres are structures responsible for maintaining chromosome stability through two main complexes: the telomerase complex that elongates the telomeres, and the shelterin complex that protects and caps the chromosome ends.^[1] These complexes are formed by several proteins and we currently know that mutations in some of the genes encoding these proteins can result in disorders associated with telomere shortening.^[2] Dyskeratosis congenita is one of the best known examples; it is a telomere disease characterised by, among others, bone marrow failure, abnormal skin manifestations, and premature ageing.^[3] Other examples are idiopathic pulmonary disorder, acute myelogenous leukaemia, and aplastic anaemia.
Under normal conditions, telomeres undergo shortening with each round of DNA replication, and consequently telomeres shorten with ageing.^[4] Some studies have reported that shorter telomeres in lymphocytes are associated with increased susceptibility to common diseases of ageing and may be predictive of both malignant and non-malignant diseases.^[5] Associations between telomere length (TL) and cancer have been found for bladder,^[6] head and neck,^[5] lung^[7] and gastric cancers,^[8] while studies on breast cancer have yielded inconsistent results.^[9] Regarding ovarian cancer, previous studies have shown that telomeres are shorter and telomerase activity is increased in malignant epithelial ovarian tumour tissues.^[10] In addition, plasma-derived free DNA of ovarian cases had shorter telomeres than controls,^[11] and shorter telomeres in peripheral blood leucocytes were associated with risk of serous ovarian adenocarcinoma.^[12] However, another very recent study found no differences in mean TL in lymphocytes between a group of ovarian cancer cases and controls, although they were able to find a significant association between different single nucleotide polymorphisms (SNPs) in the TERT gene and ovarian cancer risk.^[13]
Regarding familial breast and ovarian cancer (FBOC), we recently demonstrated that familial breast cancer, with or without mutations in the BRCA1 or BRCA2 genes, was characterised by shorter telomeres compared with sporadic breast cancer and the control population.^[14] These findings suggest that BRCA1 and BRCA2 are telomere modifying genes, probably related to the role they play in telomere maintenance.^[15]
In the present study, we retrospectively analysed TL in blood leucocytes from both hereditary and sporadic ovarian cancer cases, to investigate further the possible role of shorter TL as a risk factor for ovarian cancer. Our study demonstrates that both familial and sporadic ovarian cancer cases have shorter telomeres than controls and that there is a significant association between short telomeres and ovarian cancer risk.

Section 1 of 4