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Whole exome sequencing of rare aggressive breast cancer histologies

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Abstract

Little is known about mutational landscape of rare breast cancer (BC) subtypes. The aim of the study was to apply next generation sequencing to three different subtypes of rare BCs in order to identify new genes related to cancer progression. We performed whole exome and targeted sequencing of 29 micropapillary, 23 metaplastic, and 27 pleomorphic lobular BCs. Micropapillary BCs exhibit a profile comparable to common BCs: PIK3CA, TP53, GATA3, and MAP2K4 were the most frequently mutated genes. Metaplastic BCs presented a high frequency of TP53 (78 %) and PIK3CA (48 %) mutations and were recurrently mutated on KDM6A (13 %), a gene involved in histone demethylation. Pleomorphic lobular carcinoma exhibited high mutation rate of PIK3CA (30 %), TP53 (22 %), and CDH1 (41 %) and also presented mutations in PYGM, a gene involved in glycogen metabolism, in 8 out of 27 samples (30 %). Further analyses of publicly available datasets showed that PYGM is dramatically underexpressed in common cancers as compared to normal tissues and that low expression in tumors is correlated with poor relapse-free survival. Immunohistochemical staining on formalin-fixed paraffin-embedded tissues available in our cohort of patients confirmed higher PYGM expression in normal breast tissue compared to equivalent tumoral zone. Next generation sequencing methods applied on rare cancer subtypes can serve as a useful tool in order to uncover new potential therapeutic targets. Sequencing of pleomorphic lobular carcinoma identified a high rate of alterations in PYGM. These findings emphasize the role of glycogen metabolism in cancer progression.

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Acknowledgments

This work was supported by the Donation Program of “Opération Parrain-Chercheur” and Grants from Odyssea, Dassault Foundation, DUERTECC/EURONCO (Diplôme Universitaire Européen de Recherche Translationnelle et Clinique en Cancérologie) and the Monica Boscolo 2012 Research Grant. We thank Yuki Takahashi for proofreading this manuscript.

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    Authors and Affiliations

    1. Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, 35121, Padua, Italy

      Maria Vittoria Dieci, Valentina Guarneri & Pierfranco Conte

    2. Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128, Padua, Italy

      Maria Vittoria Dieci, Valentina Guarneri & Pierfranco Conte

    3. INSERM Unit U981, 114 rue E Vaillant, 94805, Villejuif, France

      Veronika Smutná, Véronique Scott, Cécile Vicier, Olivia Fromigué, Fabrice André & Celine Lefebvre

    4. Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France

      Veronika Smutná, Véronique Scott, Cécile Vicier, Suzette Delaloge, Ludovic Lacroix, Olivia Fromigué, Fabrice André & Celine Lefebvre

    5. Univ. Paris Sud, 63 rue Gabriel Péri, 94270, Le Kremlin-Bicêtre, France

      Veronika Smutná, Cécile Vicier & Fabrice André

    6. BGI-Shenzhen, Shenzhen, 518083, China

      Guangliang Yin & Ran Xu

    7. Department of Medical Biology and Pathology, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France

      Philippe Vielh & Marie-Christine Mathieu

    8. Laboratory of Translational Research and Biobank, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France

      Philippe Vielh, Melanie Laporte, Francoise Drusch & Ludovic Lacroix

    9. Department of Medical Oncology, Gustave Roussy, 114 rue E Vaillant, 94805, Villejuif, France

      Suzette Delaloge & Fabrice André

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    1. Maria Vittoria Dieci
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    Maria Vittoria Dieci and Veronika Smutná have equally contributed as first authors.

    Celine Lefebvre and Fabrice André have equally contributed as senior scientists.

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    Dieci, M.V., Smutná, V., Scott, V. et al. Whole exome sequencing of rare aggressive breast cancer histologies. Breast Cancer Res Treat 156, 21–32 (2016). https://doi.org/10.1007/s10549-016-3718-y

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