SBA classification is still based on the location of the primary tumor, without genetic information. in the current study, an extensive genetic profile of SBA, was performed in order to identify and quantify targetable alterations for a future precision medicine in SBA. Clinical-pathological information for 24 patients affected by SBA were retrospectively reviewed. Whole genome analysis of the primary tumors was performed by the FOUNDATION Cdx technology. We carried out a functional enrichment analysis of the mutated genes with BioPlanet. Integrative clustering analysis revealed three distinct subtypes characterized by different genomic alterations. Cluster 1exhibited significant correlations with MSI status, high TMB, celiac disease and Jejunual site.We defined cluster 1 as “immunological subtype” (29.2% of patients). Driver mutations in this subtype suggest that 100% of patients may benefit from immunotherapy. Enrichment analysis of cluster 2 highlighted that the main affected pathway was that of homologous DNA pairing and strand exchange (16.7% of patients). We defined this cluster as “DNA Damage Repair (DDR) like”. On the basis of these driver molecular alterations, 100% of patients could benefit from PARPi. Finally, Cluster 3 had no significant correlations with clinical-pathological characteristics (54.1% of patients). Enrichment analysis revealed that this cluster has remarkable similarities with CRA genomic profile, so we defined it as “Colon-like”. SBA is a genetically distinct tumor entity and deep mutation heterogeneity indicates that different driver genes play a role in the biology of these tumors. The identification of clusters based on genetic profile suggest the possibility to go beyond chemotherapy in several patients.

Extensive molecular reclassification: new perspectives in small bowel adenocarcinoma?

Casadei-Gardini A.;Orsi G.;Cascinu S.
2021-01-01

Abstract

SBA classification is still based on the location of the primary tumor, without genetic information. in the current study, an extensive genetic profile of SBA, was performed in order to identify and quantify targetable alterations for a future precision medicine in SBA. Clinical-pathological information for 24 patients affected by SBA were retrospectively reviewed. Whole genome analysis of the primary tumors was performed by the FOUNDATION Cdx technology. We carried out a functional enrichment analysis of the mutated genes with BioPlanet. Integrative clustering analysis revealed three distinct subtypes characterized by different genomic alterations. Cluster 1exhibited significant correlations with MSI status, high TMB, celiac disease and Jejunual site.We defined cluster 1 as “immunological subtype” (29.2% of patients). Driver mutations in this subtype suggest that 100% of patients may benefit from immunotherapy. Enrichment analysis of cluster 2 highlighted that the main affected pathway was that of homologous DNA pairing and strand exchange (16.7% of patients). We defined this cluster as “DNA Damage Repair (DDR) like”. On the basis of these driver molecular alterations, 100% of patients could benefit from PARPi. Finally, Cluster 3 had no significant correlations with clinical-pathological characteristics (54.1% of patients). Enrichment analysis revealed that this cluster has remarkable similarities with CRA genomic profile, so we defined it as “Colon-like”. SBA is a genetically distinct tumor entity and deep mutation heterogeneity indicates that different driver genes play a role in the biology of these tumors. The identification of clusters based on genetic profile suggest the possibility to go beyond chemotherapy in several patients.
2021
ATM
BRCA
Celiac disease
Immunotherapy
Microsatellite instability
Molecular
NF43
Parpi
Tumor mutational burden
Adenocarcinoma
Adult
Aged
Aged, 80 and over
Cluster Analysis
DNA Repair
Duodenal Neoplasms
Female
Humans
Intestinal Neoplasms
Intestine, Small
Male
Microsatellite Instability
Middle Aged
Mutation
Retrospective Studies
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/125277
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