Oncotarget

Research Papers:

FOXL2 homozygous genotype and chromosome instability are associated with recurrence in adult granulosa cell tumors of the ovary

Francois Kraus, Julie Dremaux, Wajd Altakfi, Magalie Goux, Léa Pontois, Henri Sevestre and Stéphanie Trudel _

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Oncotarget. 2020; 11:419-428. https://doi.org/10.18632/oncotarget.27447

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Abstract

Francois Kraus1,3, Julie Dremaux1,2, Wajd Altakfi4, Magalie Goux1, Léa Pontois2, Henri Sevestre4 and Stéphanie Trudel1,2

1 EA4666, LNPC, Université de Picardie Jules Verne, Amiens, France

2 Laboratoire d’Oncobiologie moléculaire, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France

3 Service de Gynécologie et Obstétrique, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France

4 Service d’Anatomie et de Cytologie Pathologiques, Centre Hospitalier Universitaire Amiens-Picardie, Amiens, France

Correspondence to:

Stéphanie Trudel,email: trudel.s@chu-toulouse.fr

Keywords: granulosa cell tumor; recurrence; FOXL2; array comparative genomic hybridization; chromosome instability

Received: September 14, 2019     Accepted: January 04, 2020     Published: January 28, 2020

ABSTRACT

Introduction: Adult granulosa cell tumors (aGCTs) are extremely rare tumors characterized by the presence of the single missense mutation (c.402 C>G, p. C134W) in the FOXL2 gene. These tumors are frequently associated with a slow, indolent disease progression and a high probability of aggressive tumor recurrence. Hence, the identification of molecular markers that are predictive of recurrence and/or aggressive behavior would be a great asset in the management of aGCT. The present study focused on the influence of the FOXL2 genotype (heterozygous or homozygous) and copy number variations (CNVs) in recurrence by comparing the primary tumor with recurrent lesions in the same patient. We performed array comparative genomic hybridization (CGH) experiments and FOXL2 genotyping by allelic discrimination on 40 tumor samples. Results and Discussion: In array CGH results of recurrent tumors, few samples presented the multiple chromosome losses and gains characteristic of chromosome instability (CIN). We also observed that three recurrent tumors and one primary tumor appeared to be homozygous for the FOXL2 c.402C>G mutation. Interestingly, the homozygous FOXL2 genotype was correlated with a shorter time to relapse. A change in the FOXL2 genotype in cases of recurrence was correlated with the appearance of CIN. Conclusion: Despite the small number of matching primary and recurrent tumors analyzed here, the present study is the first to have shown that the FOXL2 homozygous genotype and CIN are prevalent in recurrent aGCTs. The two mechanisms are probably linked, and both almost certainly have a role in the molecular transformation of aGCTs.


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