Genetic landscapes of breast tumors by next-generation sequencing with focus on less common types and genotype-phenotype correlations.

Abstract

Next-generation sequencing (NGS) has transformed our understanding of oncogenic pathways and mutational processes underlying many breast tumors. Although large-scale NGS studies included mostly common invasive breast carcinomas, the genetic landscapes of several less common or rare special histologic types and other breast tumors have now also been elucidated. Many of these lesions harbor highly specific types of mutations or rearrangements/gene fusions, including invasive lobular carcinoma, tall cell carcinoma with reversed polarity, most salivary gland-like neoplasms, fibroepithelial neoplasms, and mesenchymal tumors such as fibromatosis, nodular fasciitis, and dermatofibrosarcoma protuberans. In some cases, surrogate immunohistochemical or RNA in situ hybridization markers evaluable by light microscopy have been shown to correlate with the underlying genetic alterations. Angiosarcomas and other special breast cancer subtypes, such as triple negative apocrine carcinomas, metaplastic carcinomas, and a subset of ER-positive carcinomas (mucinous and micropapillary carcinomas, neuroendocrine neoplasms) have not been associated with specific genetic underpinnings but are enriched for certain genetic features and oncogenic pathways. The identification of characteristic genetic alterations or their molecular surrogates can be useful to establish an accurate diagnosis, and in some cases, may point to potentially actionable therapeutic targets. This review aims to summarize the genetic landscapes of less common benign and malignant breast tumors, with special attention to genotype-phenotype correlations and to the diagnostic utility of genetics and surrogate markers when applicable. BRCA1/2-associated breast carcinomas will also be discussed due to the association of so-called BRCAness with basal-like histology.