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Research Highlight | May 18, 2017

B.C. team study detects rare ovarian cancer mutation in ctDNA of patients


A study examining the circulating tumour DNA (ctDNA) of women with a rare ovarian cancer has been successful in detecting the mutation which is the defining feature of adult granulosa cell tumours (AGCTs) in the plasma of patients.

The finding by a B.C. team studying rare and forme fruste tumours is important in that it may help to identify women at risk of relapse for the disease, as well as to provide a non-invasive way to monitor patients in follow-up. Their work was published in the Journal of Molecular Diagnostics (January 2017).

FOXL2 402C>G (C134W) is the pathognomonic mutation found in these ovarian tumours, which affect three to five per cent of women diagnosed with the disease. AGCT is typically slow-growing and indolent, with a 97 per cent, five-year disease-specific survival rate for the majority of women with early Stage I tumours. However, disease recurrence occurs in 30 per cent of women within four to 10 years, and 50 to 70 per cent of this cohort will eventually die of the disease. Identifying ways to prevent relapse and improve monitoring for relapse will improve outcomes for these patients.

The team (led by Dr. David Huntsman) developed a specific digital droplet PCR (ddPCR) assay to apply to circulating cell-free DNA extracted from 120 serial plasma samples of 35 patients from Helsinki, Finland and Vancouver. FOXL2 ctDNA mutations were detected in the plasma of 12 of 33 AGCT patients (36 per cent) with both primary (35 per cent) and recurrent tumours (19 per cent). The ctDNA mutation was detected in four patients without clinical disease, of which one relapsed during follow-up.

Tumour size was identified as a factor in determining ctDNA mutation positivity and the team noted that tumour size was significantly smaller in the ctDNA mutation-negative cases. The team made recommendations for future studies pertaining to the amount of plasma needed and its isolation upon collection of the patient blood samples to ensure the quality of the cell-free DNA and to increase the yield of the ctDNA, thereby increasing the sensitivity and clinical applicability of the assay.

The present study (first author Anniina Färkkilä) not only offers a non-invasive method of detecting AGCT via liquid biopsies, but may also be able to detect recurrence before the onset of clinical symptoms or elevation of serum marker levels. Ideally, this method could indicate the presence of low-level metastatic tumour cells and highlight patients at increased risk for relapse.

Study: FOXL2 402C>G Mutation Can Be Identified in the Circulating Tumor DNA of Patients with Adult-Type Granulosa Cell Tumor

Authors: Anniina Färkkilä, Melissa K. McConechy, Winnie Yang, Aline Talhouk, Ying Ng, Amy Lum, Ryan D. Morin, Kevin Bushell, Annika Riska, Jessica N. McAlpine, C. Blake Gilks Leila Unkila-Kallio, Mikko Anttonen, and David G. Huntsman.

Funding: Supported by grants including the Terry Fox Research Institute grant 1021 (The Terry Fox New Frontiers Program Project grant in the Genomics of Forme Fruste Tumors: New Vistas on Cancer Biology and Treatment) (M.K.M.)

TFRI Links, Spring 2017