Loss of Primary Cilia Potentiates <i>BRAF/MAPK</i> Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (<i>CROCC</i>) 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 <i>SMARCB1</i> and Ciliary Rootlet Coiled-Coil (<i>CROCC</i>). We here investigate...
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MDPI AG
2023-04-01
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| Online Access: | https://www.mdpi.com/2073-4425/14/5/984 |
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| author | Andrea Remo Federica Grillo Luca Mastracci Michele Simbolo Matteo Fassan Maria Paola Cecchini Giuseppe Miscio Antonio Sassano Paola Parente Alessandro Vanoli Giovanna Sabella Guido Giordano Emanuele Damiano Urso Luigi Cerulo Aldo Scarpa Francesco Fiorica Massimo Pancione |
| author_facet | Andrea Remo Federica Grillo Luca Mastracci Michele Simbolo Matteo Fassan Maria Paola Cecchini Giuseppe Miscio Antonio Sassano Paola Parente Alessandro Vanoli Giovanna Sabella Guido Giordano Emanuele Damiano Urso Luigi Cerulo Aldo Scarpa Francesco Fiorica Massimo Pancione |
| author_sort | Andrea Remo |
| collection | DOAJ |
| description | 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 <i>SMARCB1</i> and Ciliary Rootlet Coiled-Coil (<i>CROCC</i>). 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 <i>BRAF</i> 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. |
| first_indexed | 2024-03-11T03:43:11Z |
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| id | doaj.art-f4456b4ea4294361885c722c5609db5c |
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| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T03:43:11Z |
| publishDate | 2023-04-01 |
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| record_format | Article |
| series | Genes |
| spelling | doaj.art-f4456b4ea4294361885c722c5609db5c2023-11-18T01:28:52ZengMDPI AGGenes2073-44252023-04-0114598410.3390/genes14050984Loss of Primary Cilia Potentiates <i>BRAF/MAPK</i> Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (<i>CROCC</i>) AlterationsAndrea Remo0Federica Grillo1Luca Mastracci2Michele Simbolo3Matteo Fassan4Maria Paola Cecchini5Giuseppe Miscio6Antonio Sassano7Paola Parente8Alessandro Vanoli9Giovanna Sabella10Guido Giordano11Emanuele Damiano Urso12Luigi Cerulo13Aldo Scarpa14Francesco Fiorica15Massimo Pancione16Pathology Unit, Services Department, ULSS9 “Scaligera”, 37122 Verona, ItalyAnatomic Pathology, Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa and Ospedale Policlinico San Martino, 16132 Genoa, ItalyAnatomic Pathology, Department of Integrated Surgical and Diagnostic Sciences (DISC), University of Genoa and Ospedale Policlinico San Martino, 16132 Genoa, ItalyDepartment of Diagnostic and Public Health, Section of Pathology, University of Verona, 37135 Verona, ItalyDepartment of Medicine (DIMED), Surgical Pathology Unit, University of Padua, 35128 Padua, ItalyDepartment of Neurosciences, Biomedicine and Movement Sciences, Anatomy and Histology Section, University of Verona, 37135 Verona, ItalyUnit of Pathology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, ItalyUnit of Pathology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, ItalyUnit of Pathology, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, ItalyAnatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, ItalyU.O.C. Oncologia Medica, Ospedali Riuniti Azienda Ospedaliera Universitaria, 71100 Foggia, ItalyDepartment of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35128 Padua, ItalyDepartment of Sciences and Technologies, University of Sannio, 82100 Benevento, ItalyDepartment of Diagnostic and Public Health, Section of Pathology, University of Verona, 37135 Verona, ItalyRadiotherapy Unit, Oncology Department, ULSS9 “Scaligera”, 37122 Verona, ItalyDepartment of Sciences and Technologies, University of Sannio, 82100 Benevento, ItalyA 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 <i>SMARCB1</i> and Ciliary Rootlet Coiled-Coil (<i>CROCC</i>). 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 <i>BRAF</i> 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.https://www.mdpi.com/2073-4425/14/5/984rhabdoid colorectal tumorsrare cancersCiliary Rootlet Coiled-Coil (CROCC)<i>SMARCB1</i> |
| spellingShingle | Andrea Remo Federica Grillo Luca Mastracci Michele Simbolo Matteo Fassan Maria Paola Cecchini Giuseppe Miscio Antonio Sassano Paola Parente Alessandro Vanoli Giovanna Sabella Guido Giordano Emanuele Damiano Urso Luigi Cerulo Aldo Scarpa Francesco Fiorica Massimo Pancione Loss of Primary Cilia Potentiates <i>BRAF/MAPK</i> Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (<i>CROCC</i>) Alterations Genes rhabdoid colorectal tumors rare cancers Ciliary Rootlet Coiled-Coil (CROCC) <i>SMARCB1</i> |
| title | Loss of Primary Cilia Potentiates <i>BRAF/MAPK</i> Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (<i>CROCC</i>) Alterations |
| title_full | Loss of Primary Cilia Potentiates <i>BRAF/MAPK</i> Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (<i>CROCC</i>) Alterations |
| title_fullStr | Loss of Primary Cilia Potentiates <i>BRAF/MAPK</i> Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (<i>CROCC</i>) Alterations |
| title_full_unstemmed | Loss of Primary Cilia Potentiates <i>BRAF/MAPK</i> Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (<i>CROCC</i>) Alterations |
| title_short | Loss of Primary Cilia Potentiates <i>BRAF/MAPK</i> Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (<i>CROCC</i>) Alterations |
| title_sort | loss of primary cilia potentiates i braf mapk i pathway activation in rhabdoid colorectal carcinoma a series of 21 cases showing ciliary rootlet coiledcoil i crocc i alterations |
| topic | rhabdoid colorectal tumors rare cancers Ciliary Rootlet Coiled-Coil (CROCC) <i>SMARCB1</i> |
| url | https://www.mdpi.com/2073-4425/14/5/984 |
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