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Master Thesis

Signification des variants génétiques à faible ratio allélique détectés par séquençage à haut débit dans le cadre du diagnostic moléculaire des prédispositions aux cancers du sein et de l'ovaire : mosaïque, hématopoïèse clonale ou ADN tumoral circulant

Abstract : Since the new recommendations of the « Groupe Génétique et Cancer » (GGC) to perform a panel of 13 genes (including BRCA1, BRCA2 and TP53), for the diagnosis of breast and ovarian cancers predispositions, deleterious variants of low variant allele fraction (VAF) are regularly detected. It raises the question of the differential diagnoses of mosaic neomutation, clonal hematopoiesis (CH), and circulating tumor DNA (ctDNA). To answer this question, a search of patients with low VAF variants was performed on 2007 index cases analyzed by high throughput sequencing. The presence of these variants was verified by Sanger sequencing and/or SNaPshot on different available tissues such as blood, oral smear and tumor. Among the 20 patients with potentially pathogenic low VAF variants, it was possible to document a case of BRCA1 mosaic, to detect ctDNA in a patient carrying a TP53 and a PTEN variant with a VAF close to 30%, and 9 cases of CH. For the other patients, the preferred hypothesis was CH subject to accessibility to different tissues. More women were diagnosed with ovarian cancer in carriers of low VAF TP53 variants (11/18) relative to the control group (310/1388) (p < 0 .001) and they were older (67.6 vs 55.7 years, p < 0.001). This study highlights the complexity of interpreting these variants. Mosaic remains a rare event that should be explored before testing the offspring in order to avoid traumatic diagnostic errors that would result from the presence of HC or ctDNA, particularly in the cases of TP53 variants.
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Master Thesis
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https://dumas.ccsd.cnrs.fr/dumas-02331669
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Submitted on : Thursday, October 24, 2019 - 2:26:58 PM
Last modification on : Friday, October 23, 2020 - 4:57:49 PM
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  • HAL Id : dumas-02331669, version 1

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Flavie Boulouard. Signification des variants génétiques à faible ratio allélique détectés par séquençage à haut débit dans le cadre du diagnostic moléculaire des prédispositions aux cancers du sein et de l'ovaire : mosaïque, hématopoïèse clonale ou ADN tumoral circulant. Médecine humaine et pathologie. 2019. ⟨dumas-02331669⟩

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