Journal Article

Loss of Primary Cilia Potentiates BRAF/MAPK Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (CROCC) Alterations

Pancione, Massimo, Mastracci, Luca, Sassano, Antonio, Fassan, Matteo, Cecchini, Maria Paola, Fiorica, Francesco, Miscio, Giuseppe, Parente, Paola, Sabella, Giovanna, Giordano, Guido, Urso, Emanuele Damiano, Scarpa, Aldo, Remo, Andrea, Simbolo, Michele, Grillo, Federica, Vanoli, Alessandro, Cerulo, Luigi

2023

Overview

A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and immunophenotypic profiling of 21 RCTs using immunohistochemistry and next-generation sequencing. Mismatch repair-deficient phenotypes were identified in 60% of RCTs. Similarly, a large proportion of cancers exhibited the combined marker phenotype (CK7-/CK20-/CDX2-) not common to classical adenocarcinoma variants. More than 70% of cases displayed aberrant activation of the mitogen-activated protein kinase (MAPK) pathway with mutations prevalently in BRAF V600E. SMARCB1/INI1 expression was normal in a large majority of lesions. In contrast, ciliogenic markers including CROCC and γ-tubulin were globally altered in tumors. Notably, CROCC and γ-tubulin were observed to colocalize in large cilia found on cancer tissues but not in normal controls. Taken together, our findings indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs and, therefore, may constitute a novel therapeutic target.

• Publisher: MDPI AG,MDPI
• Subject: Adenocarcinoma / aggression / Aggressive behavior / Antibodies / Antigens / CDX2 protein / Cell cycle / Chemotherapy / Cilia / Cilia - genetics / Cilia - metabolism / Cloning / Colon / Colorectal carcinoma / colorectal neoplasms / Colorectal Neoplasms - pathology / Cytoskeletal Proteins / Genomes / Humans / Hypotheses / Immunohistochemistry / Localization / MAP kinase / Medical prognosis / Mismatch repair / mitogen-activated protein kinase / Mitogen-Activated Protein Kinases - genetics / Next-generation sequencing / phenotype / Phenotypes / Proto-Oncogene Proteins B-raf - genetics / Therapeutic targets / therapeutics / Tubulin / Tumors