Genomic landscapes of breast fibroepithelial tumors

Abstract

Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications.

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

“…Alterations of SETD2, PBRM1, and SMARCC1 have been linked to several human malignancies (30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Briefly, disruptions of the SETD2 gene have been frequently observed in clear cell renal cell carcinomas (ccRCC), gliomas, chronic lymphocytic leukemia, breast fibroepithelial tumors, gastro-intestinal stromal tumors, and melanomas (30)(31)(32)(33)(34)(35)(36)(37).…”

“…Briefly, disruptions of the SETD2 gene have been frequently observed in clear cell renal cell carcinomas (ccRCC), gliomas, chronic lymphocytic leukemia, breast fibroepithelial tumors, gastro-intestinal stromal tumors, and melanomas (30)(31)(32)(33)(34)(35)(36)(37). PBRM1 is one of the most frequently mutated genes in ccRCC (31), and its alterations were also found in cholangiocarcinomas and liver cancers (38).…”

Chronic lymphocytic leukemia: Time to go past genomics?

“…Missense mutations of MED12 are associated with X-linked genetic syndromes [103][104][105]. Somatic mutations have been described in many solid tumors, including, hormone-associated cancers (prostate and adrenocortical carcinoma) [106,107], breast [108], uterine tumors [109]. The mutations are essentially missense mutations but fall in different parts of the protein, depending on the tumors.…”

Distant metastases in phyllodes tumours of the breast: an overview

“…Mutations in FLNA (28.0%), SETD2 (21.0%) and KMT2D (9.0%) were also discovered, which are believed to contribute to tumour progression in PTs [46]. Currently, the genomic features of primary PTs and their metastases are not well understood.…”