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

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 and Ciliary Rootlet Coiled-Coil ( ). We here investigate the genetic and immunophenotypic profiling of 21 R...

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Published in:Genes 2023-04, Vol.14 (5), p.984
Main Authors: Remo, Andrea, Grillo, Federica, Mastracci, Luca, Simbolo, Michele, Fassan, Matteo, Cecchini, Maria Paola, Miscio, Giuseppe, Sassano, Antonio, Parente, Paola, Vanoli, Alessandro, Sabella, Giovanna, Giordano, Guido, Urso, Emanuele Damiano, Cerulo, Luigi, Scarpa, Aldo, Fiorica, Francesco, Pancione, Massimo
Format: Article
Language:English
Subjects:
Adenocarcinoma
Aggressive behavior
Antibodies
Antigens
CDX2 protein
Cell cycle
Chemotherapy
Cilia
Cilia - genetics
Cilia - metabolism
Cloning
Colon
Colorectal carcinoma
Colorectal Neoplasms - pathology
Cytoskeletal Proteins
Genomes
Humans
Hypotheses
Immunohistochemistry
Localization
MAP kinase
Medical prognosis
Mismatch repair
Mitogen-Activated Protein Kinases - genetics
Next-generation sequencing
Phenotypes
Proto-Oncogene Proteins B-raf - genetics
Therapeutic targets
Tubulin
Tumors
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Summary: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 and Ciliary Rootlet Coiled-Coil ( ). 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 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.
ISSN:2073-4425
2073-4425
DOI:10.3390/genes14050984