Browsing by Author "Fusco, Nicola"

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    The Birth of an Adenoid Cystic Carcinoma
    (Sage, 2015-02) Fusco, Nicola; Guerini-Rocco, Elena; Schultheis, Anne M.; Badve, Sunil S.; Reis-Filho, Jorge S.; Weigelt, Britta; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Adenoid cystic carcinoma is a rare malignancy of exocrine glands defined by the presence of a dual population of cells (epithelial and myoepithelial cells) organized in varying combinations of cribriform, tubular, and solid patterns.1,2 This neoplasm most frequently originates in the salivary glands; however, it can also occur in other anatomical sites, including the breast.1,3 More than 90% of adenoid cystic carcinomas of the breast harbor the recurrent translocation t(6;9), resulting in the MYB-NFIB fusion gene, which leads to MYB overexpression.4 Adenoid cystic carcinoma in situ has been described in the breast; however, its identifica-tion is not trivial.3 Here, we illustrate an in situ adenoid cystic carcinoma partially involving a mammary duct in a 68-year-old woman with primary adenoid cystic carci-noma of the right breast. The double population of cells composing this intraductal lesion can be appreciated by its immunohistochemical profile (Figure 1). Given that the neoplastic cells of the in situ lesion already express MYB, our findings are consistent with the notion that MYB overexpression is an early event in the tumorigen-esis of adenoid cystic carcinomas.4,5
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    Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer
    (SpringerNature, 2016-11) Fusco, Nicola; Geyer, Felipe C.; De Filippo, Maria R.; Martelotto, Luciano G.; Piscuoglio, Salvatore; Guerini-Rocco, Elena; Schultheis, Anne M.; Fuhrmann, Laetitia; Wang, Lu; Jungbluth, Achim A.; Burke, Kathleen A.; Lim, Raymond S.; Vincent-Salomon, Anne; Bamba, Masamichi; Moritani, Suzuko; Badve, Sunil S.; Ichihara, Shu; Ellis, Ian O.; Reis-Filho, Jorge S.; Weigelt, Britta; Ng, Charlotte K.Y.; Department of Pathology and Laboratory Medicine, IU School of Medicine
    Adenoid cystic carcinoma of the breast is a rare histologic type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Whilst the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intra-tumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple-negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by MYB-NFIB fusion gene, and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple-negative breast cancer of no special type may involve the selection of neoplastic clones and/ or the acquisition of additional genetic alterations.
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    MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB–NFIB fusion gene
    (Wiley, 2017) Kim, Jisun; Geyer, Felipe C.; Martelotto, Luciano G.; Ng, Charlotte K. Y.; Lim, Raymond S.; Selenica, Pier; Li, Anqi; Pareja, Fresia; Fusco, Nicola; Edelweiss, Marcia; Kumar, Rahul; Gularte-Merida, Rodrigo; Forbes, Andre N.; Khurana, Ekta; Mariani, Odette; Badve, Sunil; Vincent-Salomon, Anne; Norton, Larry; Reis-Filho, Jorge S.; Weigelt, Britta; Pathology and Laboratory Medicine, School of Medicine
    Breast adenoid cystic carcinoma (AdCC), a rare type of triple-negative breast cancer, has been shown to be driven by MYB pathway activation, most often underpinned by the MYB–NFIB fusion gene. Alternative genetic mechanisms, such as MYBL1 rearrangements, have been reported in MYB–NFIB-negative salivary gland AdCCs. Here we report on the molecular characterization by massively parallel sequencing of four breast AdCCs lacking the MYB–NFIB fusion gene. In two cases, we identified MYBL1 rearrangements (MYBL1–ACTN1 and MYBL1–NFIB), which were associated with MYBL1 overexpression. A third AdCC harboured a high-level MYB amplification, which resulted in MYB overexpression at the mRNA and protein levels. RNA-sequencing and whole-genome sequencing revealed no definite alternative driver in the fourth AdCC studied, despite high levels of MYB expression and the activation of pathways similar to those activated in MYB–NFIB-positive AdCCs. In this case, a deletion encompassing the last intron and part of exon 15 of MYB, including the binding site of ERG-1, a transcription factor that may downregulate MYB, and the exon 15 splice site, was detected. In conclusion, we demonstrate that MYBL1 rearrangements and MYB amplification probably constitute alternative genetic drivers of breast AdCCs, functioning through MYBL1 or MYB overexpression. These observations emphasize that breast AdCCs probably constitute a convergent phenotype, whereby activation of MYB and MYBL1 and their downstream targets can be driven by the MYB–NFIB fusion gene, MYBL1 rearrangements, MYB amplification, or other yet to be identified mechanisms. Copyright © 2017 Pathological Society of Great Britain and Ireland.