An Insight Into the Driver Mutations and Molecular Mechanisms Underlying Mucinous Adenocarcinoma of the Rectum.
Adenocarcinoma
/ diagnosis
Adenocarcinoma, Mucinous
/ diagnosis
Aged
Cohort Studies
DNA Mismatch Repair
/ genetics
Drug Resistance, Neoplasm
/ genetics
Female
Genes, Tumor Suppressor
Humans
Immunohistochemistry
/ methods
Male
Middle Aged
Molecular Biology
/ methods
Mutation
Neoadjuvant Therapy
/ statistics & numerical data
Neoplasm Staging
Oncogenes
/ genetics
Proto-Oncogene Proteins B-raf
/ genetics
Proto-Oncogene Proteins p21(ras)
/ genetics
Rectal Neoplasms
/ pathology
Whole Genome Sequencing
/ methods
Journal
Diseases of the colon and rectum
ISSN: 1530-0358
Titre abrégé: Dis Colon Rectum
Pays: United States
ID NLM: 0372764
Informations de publication
Date de publication:
01 06 2021
01 06 2021
Historique:
entrez:
6
5
2021
pubmed:
7
5
2021
medline:
8
10
2021
Statut:
ppublish
Résumé
Mucinous adenocarcinoma of the rectum accounts for 10% of all rectal cancers and has an impaired response to neoadjuvant chemoradiotherapy and worse overall survival. To date, insufficient genomic research has been performed on this histological subtype. This study aims to define the mismatch repair deficiency rate and the driver mutations underpinning mucinous adenocarcinoma of the rectum and to compare it with rectal adenocarcinoma not otherwise specified. Immunohistochemistry and sequencing were performed on tumor samples from our tumor biobank. This study was conducted across 2 tertiary referral centers. Patients with mucinous adenocarcinoma and rectal adenocarcinoma not otherwise specified who underwent rectal resection between 2008 and 2018 were included. Mismatch repair status was performed by immunohistochemical staining. Mutations in the panel of oncogenes and tumor suppressor genes were determined by sequencing on the MiSeq V3 platform. The study included 33 patients with mucinous adenocarcinoma of the rectum and 100 patients with rectal adenocarcinoma not otherwise specified. Those with mucinous adenocarcinoma had a mismatch repair deficiency rate of 12.1% compared to 2.0% in the adenocarcinoma not otherwise specified cohort (p = 0.04). Mucinous adenocarcinoma and adenocarcinoma not otherwise specified rectal tumors had similar mutation frequencies in most oncogenes and tumor suppressor genes. No difference was found in the KRAS mutation rate (50.0% vs 37.1%, p = 0.29) or BRAF mutation rate (6.7% vs 3.1%, p = 0.34) between the cohorts. No difference was found between the cohorts regarding recurrence-free (p = 0.29) or overall survival (p = 0.14). The major limitations of this study were the use of formalin-fixed, paraffin-embedded tissue over fresh-frozen tissue and the small number of patients included, in particular, in the mucinous rectal cohort. Most mucinous rectal tumors develop and progress along the chromosomal instability pathway. Further research in the form of transcriptomics, proteomics, and analysis of the effects of the mucin barrier may yield valuable insights into the mechanisms of resistance to chemoradiotherapy in this cohort. See Video Abstract at http://links.lww.com/DCR/B464. ANTECEDENTES:El adenocarcinoma mucinoso del recto, representa el 10% de todos los cánceres rectales y tiene una respuesta deficiente a la quimioradioterapia neoadyuvante y una peor supervivencia en general. A la fecha, se han realizado muy pocas investigaciones genómicas sobre este subtipo histológico.OBJETIVO:Definir la tasa de deficiencia en la reparación de desajustes y mutaciones impulsoras, que sustentan el adenocarcinoma mucinoso del recto y compararlo con el adenocarcinoma rectal no especificado de otra manera.DISEÑO:Se realizaron inmunohistoquímica y secuenciación en muestras tumorales de nuestro biobanco de tumores.AJUSTE:El estudio se realizó en dos centros de referencia terciarios.PACIENTES:Se incluyeron pacientes con adenocarcinoma mucinoso y adenocarcinoma no especificado de otra manera, sometidos a resección rectal entre 2008 y 2018.PRINCIPALES MEDIDAS DE RESULTADO:El estado de reparación de desajustes se realizó mediante tinción inmunohistoquímica. Las mutaciones en el panel de oncogenes y genes supresores de tumores, se determinaron mediante secuenciación en la plataforma MiSeq V3.RESULTADOS:El estudio incluyó a 33 pacientes con adenocarcinoma mucinoso del recto y 100 pacientes con adenocarcinoma del recto no especificado de otra manera. Aquellos con adenocarcinoma mucinoso, tenían una tasa de deficiencia de reparación de desajustes del 12,1% en comparación con el 2,0% en la cohorte de adenocarcinoma no especificado de otra manera (p = 0,04). El adenocarcinoma mucinoso y el adenocarcinoma no especificado de otra manera, tuvieron frecuencias de mutación similares en la mayoría de los oncogenes y genes supresores de tumores. No se encontraron diferencias en la tasa de mutación de KRAS (50,0% frente a 37,1%, p = 0,29) o la tasa de mutación de BRAF (6,7% frente a 3,1%, p = 0,34) entre las cohortes. No se encontraron diferencias entre las cohortes con respecto a la supervivencia libre de recurrencia (p = 0,29) o la supervivencia global (p = 0,14).LIMITACIONES:Las mayores limitaciones de este estudio, fueron el uso de tejido embebido en parafina y fijado con formalina, sobre el tejido fresco congelado y el pequeño número de pacientes incluidos, particularmente en la cohorte mucinoso rectal.CONCLUSIONES:La mayoría de los tumores rectales mucinosos se desarrollan y progresan a lo largo de la vía de inestabilidad cromosómica. La investigación adicional en forma transcriptómica, proteómica y análisis de los efectos de la barrera de la mucina, puede proporcionar información valiosa sobre los mecanismos de resistencia a la quimioradioterapia, en esta cohorte. Consulte Video Resumen en http://links.lww.com/DCR/B464.
Sections du résumé
BACKGROUND
Mucinous adenocarcinoma of the rectum accounts for 10% of all rectal cancers and has an impaired response to neoadjuvant chemoradiotherapy and worse overall survival. To date, insufficient genomic research has been performed on this histological subtype.
OBJECTIVE
This study aims to define the mismatch repair deficiency rate and the driver mutations underpinning mucinous adenocarcinoma of the rectum and to compare it with rectal adenocarcinoma not otherwise specified.
DESIGN
Immunohistochemistry and sequencing were performed on tumor samples from our tumor biobank.
SETTINGS
This study was conducted across 2 tertiary referral centers.
PATIENTS
Patients with mucinous adenocarcinoma and rectal adenocarcinoma not otherwise specified who underwent rectal resection between 2008 and 2018 were included.
MAIN OUTCOME MEASURES
Mismatch repair status was performed by immunohistochemical staining. Mutations in the panel of oncogenes and tumor suppressor genes were determined by sequencing on the MiSeq V3 platform.
RESULTS
The study included 33 patients with mucinous adenocarcinoma of the rectum and 100 patients with rectal adenocarcinoma not otherwise specified. Those with mucinous adenocarcinoma had a mismatch repair deficiency rate of 12.1% compared to 2.0% in the adenocarcinoma not otherwise specified cohort (p = 0.04). Mucinous adenocarcinoma and adenocarcinoma not otherwise specified rectal tumors had similar mutation frequencies in most oncogenes and tumor suppressor genes. No difference was found in the KRAS mutation rate (50.0% vs 37.1%, p = 0.29) or BRAF mutation rate (6.7% vs 3.1%, p = 0.34) between the cohorts. No difference was found between the cohorts regarding recurrence-free (p = 0.29) or overall survival (p = 0.14).
LIMITATIONS
The major limitations of this study were the use of formalin-fixed, paraffin-embedded tissue over fresh-frozen tissue and the small number of patients included, in particular, in the mucinous rectal cohort.
CONCLUSIONS
Most mucinous rectal tumors develop and progress along the chromosomal instability pathway. Further research in the form of transcriptomics, proteomics, and analysis of the effects of the mucin barrier may yield valuable insights into the mechanisms of resistance to chemoradiotherapy in this cohort. See Video Abstract at http://links.lww.com/DCR/B464.
UNA PERCEPCIN SOBRE MUTACIONES IMPULSORAS Y MECANISMOS MOLECULARES SUBYACENTES AL ADENOCARCINOMA MUCINOSO DEL RECTO
ANTECEDENTES:El adenocarcinoma mucinoso del recto, representa el 10% de todos los cánceres rectales y tiene una respuesta deficiente a la quimioradioterapia neoadyuvante y una peor supervivencia en general. A la fecha, se han realizado muy pocas investigaciones genómicas sobre este subtipo histológico.OBJETIVO:Definir la tasa de deficiencia en la reparación de desajustes y mutaciones impulsoras, que sustentan el adenocarcinoma mucinoso del recto y compararlo con el adenocarcinoma rectal no especificado de otra manera.DISEÑO:Se realizaron inmunohistoquímica y secuenciación en muestras tumorales de nuestro biobanco de tumores.AJUSTE:El estudio se realizó en dos centros de referencia terciarios.PACIENTES:Se incluyeron pacientes con adenocarcinoma mucinoso y adenocarcinoma no especificado de otra manera, sometidos a resección rectal entre 2008 y 2018.PRINCIPALES MEDIDAS DE RESULTADO:El estado de reparación de desajustes se realizó mediante tinción inmunohistoquímica. Las mutaciones en el panel de oncogenes y genes supresores de tumores, se determinaron mediante secuenciación en la plataforma MiSeq V3.RESULTADOS:El estudio incluyó a 33 pacientes con adenocarcinoma mucinoso del recto y 100 pacientes con adenocarcinoma del recto no especificado de otra manera. Aquellos con adenocarcinoma mucinoso, tenían una tasa de deficiencia de reparación de desajustes del 12,1% en comparación con el 2,0% en la cohorte de adenocarcinoma no especificado de otra manera (p = 0,04). El adenocarcinoma mucinoso y el adenocarcinoma no especificado de otra manera, tuvieron frecuencias de mutación similares en la mayoría de los oncogenes y genes supresores de tumores. No se encontraron diferencias en la tasa de mutación de KRAS (50,0% frente a 37,1%, p = 0,29) o la tasa de mutación de BRAF (6,7% frente a 3,1%, p = 0,34) entre las cohortes. No se encontraron diferencias entre las cohortes con respecto a la supervivencia libre de recurrencia (p = 0,29) o la supervivencia global (p = 0,14).LIMITACIONES:Las mayores limitaciones de este estudio, fueron el uso de tejido embebido en parafina y fijado con formalina, sobre el tejido fresco congelado y el pequeño número de pacientes incluidos, particularmente en la cohorte mucinoso rectal.CONCLUSIONES:La mayoría de los tumores rectales mucinosos se desarrollan y progresan a lo largo de la vía de inestabilidad cromosómica. La investigación adicional en forma transcriptómica, proteómica y análisis de los efectos de la barrera de la mucina, puede proporcionar información valiosa sobre los mecanismos de resistencia a la quimioradioterapia, en esta cohorte. Consulte Video Resumen en http://links.lww.com/DCR/B464.
Identifiants
pubmed: 33955407
doi: 10.1097/DCR.0000000000001825
pii: 00003453-202106000-00007
doi:
Substances chimiques
KRAS protein, human
0
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Comparative Study
Journal Article
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
677-688Informations de copyright
Copyright © The ASCRS 2021.
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