The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas

Abstract

Purpose Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic type of breast cancer predominantly of triple-negative phenotype, and characterized by the presence of malignant cells showing squamous and/or mesenchymal differentiation. We sought to define the repertoire of somatic genetic alterations and the mutational signatures of MBCs. Experimental Design Whole-exome sequencing was performed in 35 MBCs, with 16, ten and nine classified as harboring chondroid, spindle and squamous metaplasia as the predominant metaplastic component. The genomic landscape of MBCs was compared to that of triple-negative invasive ductal carcinomas of no special type (IDC-NSTs) from The Cancer Genome Atlas. Wnt and PI3K/AKT/mTOR pathway activity was assessed using a quantitative PCR assay. Results MBCs harbored complex genomes with frequent TP53 (69%) mutations. In contrast to triple-negative IDC-NSTs, MBCs more frequently harbored mutations in PIK3CA (29%), PIK3R1 (11%), ARID1A (11%), FAT1 (11%) and PTEN (11%). PIK3CA mutations were not found in MBCs with chondroid metaplasia. Compared to triple-negative IDC-NSTs, MBCs significantly more frequently harbored mutations in PI3K/AKT/mTOR pathway-related (57% vs 22%) and canonical Wnt pathway-related (51% vs 28%) genes. MBCs with somatic mutations in PI3K/AKT/mTOR or Wnt pathway-related genes displayed increased activity of the respective pathway. Conclusion MBCs are genetically complex and heterogeneous, and are driven by a repertoire of somatic mutations distinct from that of triple-negative IDC-NSTs. Our study highlights the genetic basis and the importance of PI3K/AKT/mTOR and Wnt pathway dysregulation in MBCs, and provides a rationale for the metaplastic phenotype and the reported responses to PI3K/AKT/mTOR inhibitors in these tumors.

High rate of PIK3CA mutations but no TP53 mutations in low‐grade adenosquamous carcinoma of the breast

“…Metaplastic carcinomas show more frequent mutations in PIK3CA , PIK3R1 , PTEN (57% of cases), and Wnt pathway genes (51% of cases). PIK3CA mutations are significantly more frequently observed in spindle cell metaplastic carcinomas than in other metaplastic carcinomas . In this context, our results provide another piece of evidence for heterogeneity within the spectrum of metaplastic carcinomas.…”

“…The advent of MPS has contributed to a thorough characterisation of the genetic landscape of breast cancer . Recently, it has been demonstrated that, although metaplastic carcinomas and common forms of TNBC harbour similar mutational frequencies for TP53 , they are genetically distinct entities . Metaplastic carcinomas show more frequent mutations in PIK3CA , PIK3R1 , PTEN (57% of cases), and Wnt pathway genes (51% of cases).…”

CCN6 regulates IGF2BP2 and HMGA2 signaling in metaplastic carcinomas of the breast

“…Genomic analyses of human tumors showed that metaplastic carcinomas and non-metaplastic TNBCs share TP53 mutations [26-30]. In addition, metaplastic carcinomas harbor more frequent PI3K and Wnt pathway gene mutations than non-metaplastic TNBC [27,24]. However, specific pathways operative in spindle and squamous metaplastic carcinomas have not been reported to date.…”

Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

“…Representative formalin-fixed paraffin-embedded (FFPE) tissue sections of all ovarian tumors and of core biopsies of metastases from the advanced breast cancer patients obtained at diagnosis (patient 1109 patient) and at recurrence (patient L031) were stained with nuclear fast red and microdissected with a sterile needle under a stereomicroscope (Olympus SZ61) to ensure >80% of tumor cell content, as previously described (23). In nine ovarian cancer cases, histologically distinct regions of the primary tumor or distinct anatomical sites including omental implants were available and microdissected (median of 1 (range 1–4) anatomically distinct regions per case).…”

“…In nine ovarian cancer cases, histologically distinct regions of the primary tumor or distinct anatomical sites including omental implants were available and microdissected (median of 1 (range 1–4) anatomically distinct regions per case). Genomic DNA was extracted from tumor samples and peripheral blood leukocytes using the DNeasy Blood and Tissue Kit (Qiagen) and quantified using the Qubit Fluorometer, as previously described (23,24). …”