BRAF Mutation in Colorectal Rhabdoid and Poorly Differentiated Medullary Carcinomas

Abstract

Colorectal rhabdoid carcinomas (CRbCs) are very rare and aggressive cancers. The BRAF mutation and CpG island methylator phenotype have been reported to be common features of CRbCs. This study reviews the literature about CRbCs and analyzes the clinicopathological and molecular profiles of seven CRbCs characterized by large discohesive cells with abundant eosinophilic cytoplasm, showing hyaline inclusions and large rounded to bean-shaped nuclei. For comparison, we included four poorly differentiated medullary carcinomas (PDMCs) with focal aspects mimicking rhabdoid features. Overall survival was poor in both subsets, with 78% of patients dying of disease within 2–11 months. The main features of CRbCs were: Loss of/reduced SMARCB1/INI expression, intense vimentin immunostaining, and dense neutrophilic infiltration. The PDMCs were positive for pancytokeratin but negative for vimentin and showed moderate peritumoral/intratumoral CD8+ lymphocytes. All PDMCs showed SMARCB1(INI-1) expression. The coexistence of BRAF and TP53 mutations was observed in 80% of CRbCs and PDMCs. PDMCs always showed microsatellite instability and CpG island methylator phenotype (CIMP), while CRbCs were CIMP negative and exhibited microsatellite instability (MSI) in two out of seven cases. CRbCs are characterized by BRAF and TP53 mutations. Loss/reduced expression of nuclear SMARCB1/INI, intense vimentin immunostaining, dense neutrophilic infiltration, and low frequency of CIMP are useful markers to recognize these rare aggressive tumors.

Methylation Drivers and Prognostic Implications in Sinonasal Poorly Differentiated Carcinomas

“…A gene-targeted NGS analysis was performed on a subset of 30 DNA samples using the Human Actionable Solid Tumor Mutations QIAseq DNA Panel (DHS-101Z, Qiagen, Hilden, Germany) that analyzes 22 oncogenes ( BRAF, PDGFRA, EGFR, KRAS, NRAS, KIT, AKT1, ALK, CTNNB1, ERBB3, ESR1, FOXL2, GNA11, GNAQ, IDH1, IDH2, MET, RAF1, RET, ERBB2, PIK3CA, and TP53 ). A targeted amplicon-based library was constructed as described in a previous work of our group according to the manufacturer protocol [ 29 ]. Barcoded libraries were pooled together at 8pM and sequenced on an Ion S5 XL System (A27214, Thermo Fisher Scientific) using Ion 530 chip (Thermo Fisher Scientific).…”

Mixed Neuroendocrine/Non-neuroendocrine Neoplasm (MiNEN) of the Ovary Arising from Endometriosis: Molecular Pathology Analysis in Support of a Pathogenetic Paradigm

“…A targeted NGS analysis was performed on all the four different lesions (NEC, endometrioid carcinoma, ovarian endometriosis, and uterine EAH) and on a sample of normal tissue for comparison using the Human Actionable Solid Tumor Mutations QIAseq DNA Panel (DHS-101Z, Qiagen, Hilden, Germany) that analyses 22 oncogenes (BRAF, PDGFRA, EGFR, KRAS, NRAS, KIT, AKT1, ALK, CTNNB1, ERBB3, ESR1, FOXL2, GNA11, GNAQ, IDH1, IDH2, MET, RAF1, RET, ERBB2, PIK3CA, and TP53). A targeted amplicon-based library was constructed as described in a previous work of our group [7] according to the manufacturer's protocol. Barcoded libraries were quantified, pooled together at 8 pM, and sequenced on an Ion S5 Fig.…”

“…Barcoded libraries were quantified, pooled together at 8 pM, and sequenced on an Ion S5 Fig. 4 Results of the molecular and immunohistochemical study of alterations of cancer-related genes in the four morphologically distinct lesions find in the ovary and in the endometrium (see text for details) XL System (A27214, Thermo Fisher Scientific) using Ion 530 Chip (Thermo Fisher Scientific) as previously reported [7]. Unmapped BAM (uBAM) files were imported into the CLC Genomics Workbench (Qiagen Bioinformatics, Germany, version 12) and mapped on the Human hg19 genome.…”

“…Unmapped BAM (uBAM) files were imported into the CLC Genomics Workbench (Qiagen Bioinformatics, Germany, version 12) and mapped on the Human hg19 genome. Sequencing data were analyzed as previously reported [7] and they were filtered ensuring a coverage of at least 100 × and a variant allele frequency (VAF) of 5%.…”

SMARCB1/INI1-Deficient Poorly Differentiated Carcinoma of the Colon With Rhabdoid Features—A Rare Tumor With Serrated Phenotype: Case Report and Review of Literature

“…To date, only 44 such tumors have been reported in the literature on extensive Google Scholar and PubMed database searches and analyses of published data by 2 individual authors. 7,8 We have also summarized the salient findings of the full papers available in Table 1.…”