A plasma telomeric cell-free DNA level in unaffected women with BRCA1 or/and BRCA2 mutations: a pilot study.

Shatovisha Dey,Aditi Shendre,Hiromi Tanaka,Anna Maria Storniolo,Paige N Dahlgren,Chunyan He,Natascia Marino,Kanokwan Bishop

doi:10.18632/oncotarget.23767

Abstract

Plasma cell-free DNA (cfDNA) is a small DNA fragment circulating in the bloodstream originating from both non-tumor- and tumor-derived cells. A previous study showed that a plasma telomeric cfDNA level decreases in sporadic breast cancer patients compared to controls. Tumor suppressor gene products including BRCA1 and BRCA2 (BRCA1&2) play an important role in telomere maintenance. In this study, we hypothesized that the plasma telomeric cfDNA level is associated with the mutation status of BRCA1&2 genes. To test this hypothesis, we performed plasma telomeric cfDNA quantitative PCR (qPCR)-based assays to compare 28 women carriers of the BRCA1&2 mutation with age-matched controls of 28 healthy women. The results showed that the plasma telomeric cfDNA level was lower in unaffected BRCA1&2 mutation carriers than in age-matched controls from non-obese women (BMI < 30), while there was no association between unaffected BRCA1&2 mutation carriers and age-matched controls in obese women (BMI > 30). Moreover, the plasma telomeric cfDNA level applied aptly to the Tyrer-Cuzick model in non-obese women. These findings suggest that circulating cfDNA may detect dysfunctional telomeres derived from cells with BRCA1&2 mutations and, therefore, its level is associated with breast cancer susceptibility. This pilot study warrants further investigation to elucidate the implication of plasma telomeric cfDNA levels in relation to cancer and obesity.

Highlights

Plasma, serum, and other biofluids contain very low amounts of circulating extracellular cell-free DNA, called cfDNA. cfDNA has become an increasingly important source for the development of liquid biopsy assays for early cancer detection
The results showed that the plasma telomeric cfDNA level was lower in unaffected BRCA1 and BRCA2 (BRCA1&2) mutation carriers than in age-matched controls from non-obese women (BMI < 30), while there was no association between unaffected BRCA1&2 mutation carriers and age-matched controls in obese women (BMI > 30)
We hypothesized that a circulating telomeric cfDNA level could be affected by BRCA1&2 heterozygous mutations; the telomeric cfDNA level decreases in BRCA1&2 mutation carriers as compared to healthy controls

Summary

Introduction

Serum, and other biofluids contain very low amounts of circulating extracellular cell-free DNA, called cfDNA. cfDNA has become an increasingly important source for the development of liquid biopsy assays for early cancer detection. Current cfDNA assays have mostly focused on monitoring cancer-specific mutations or methylation changes by targeting cell-free tumor DNA (ctDNA) [2]. In this case, the assays require prior information on specific genetic or epigenetic alterations present in the original tumor lesion. We recently devised a qPCR-based cfDNA assay to measure telomeric cfDNA levels (i.e., relative amounts of [TTAGGG]n sequences) in plasma Using this assay, we reported that plasma telomeric cfDNA levels were significantly decreased in sporadic breast cancer patients www.impactjournals.com/oncotarget with no prior treatment, compared to non-cancer controls [5]. These findings suggest that telomere dysfunction (e.g., rapid telomere shortening) in body tissues might accumulate during cancer development and be associated with cancer progression, resulting in dynamic changes in the plasma telomeric cfDNA level

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