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Extensive molecular reclassification: new perspectives in small bowel adenocarcinoma?

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Andrea Casadei Gardini at Università Vita-Salute San Raffaele
Andrea Casadei Gardini
Sara Lonardi at Istituto Oncologico Veneto
Sara Lonardi
Valeria Smiroldo at Azienda Socio Sanitaria Territoriale Rhodense
Valeria Smiroldo
  • Azienda Socio Sanitaria Territoriale Rhodense
Matteo Canale at Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
Matteo Canale
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Abstract and Figures

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.
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Vol.:(0123456789)
1 3
Medical Oncology (2021) 38:17
https://doi.org/10.1007/s12032-021-01468-z
ORIGINAL PAPER
Extensive molecular reclassification: new perspectives insmall bowel
adenocarcinoma?
AndreaCasadei‑Gardini1 · SaraLonardi2,3· ValeriaSmiroldo4· MatteoCanale5· AlessandroPassardi6·
NicolaSilvestris7· GiuliaOrsi1· FlorianaNappo3,8· LorenzaRimassa4,9· MatteoFassan10· PaolaSpaggiari11·
OronzoBrunetti7· KalliopiAndrikou6· StefanoCascinu1
Received: 21 December 2020 / Accepted: 22 January 2021 / Published online: 2 February 2021
© Springer Science+Business Media, LLC, part of Springer Nature 2021
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.
Keywords Microsatellite instability· BRCA · Molecular· Celiac disease· Tumor mutational burden· NF43· ATM·
Immunotherapy· Parpi
* Andrea Casadei-Gardini
casadeigardini@gmail.com
1 Department ofMedical Oncology, Università Vita-Salute
San Raffaele, IRCCS-Ospedale San Raffaele, Via Olgettina
70, 20132Milan, Italy
2 Early Phase Clinical Trial Unit, Department ofOncology,
Veneto Institute ofOncology IOV-IRCCS, Padua, Italy
3 Medical Oncology Unit 1, Department ofOncology, Veneto
Institute ofOncology IOV - IRCCS, Padua, Italy
4 Medical Oncology andHematology Unit, Humanitas Cancer
Center; IRCCS Humanitas Research Hospital, Via Manzoni
56, 20089Rozzano, Milan, Italy
5 Biosciences Laboratory, IRCCS Istituto Romagnolo perlo
Studio dei Tumori “Dino Amadori”, 47014Meldola, Italy
6 Department ofMedical Oncology, IRCCS Istituto
Romagnolo perlo Studio dei Tumori “Dino Amadori”,
Meldola, Italy
7 Medical Oncology Unit, IRCCS Istituto Tumori “Giovanni
Paolo II” ofBari, Bari, Italy
8 Department ofSurgery, Oncology andGastroenterology,
University ofPadua, Padua, Italy
9 Department ofBiomedical Sciences, Humanitas University,
Via Rita Levi Montalcini 4, 20090PieveEmanuele, Milan,
Italy
10 Department ofMedicine (DIMED), Surgical Pathology &
Cytopathology Unit, University ofPadua, Padua, Italy
11 Department ofPathology, IRCCS Humanitas Research
Hospital, Milan, Italy
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Collecting clinic data linked to biologic data is a challenge for this rare disease. Herein we pool three databases with clinicbiologic data available (AGEO study, BIONADEGE and Casadei-Gardini study) in order to increase the power of each analysis adding value to the previous publications [10,12,14]. ...
... The BIONADEGE cohort has recruited 196 patients previously enrolled in the NADEGE cohort in 24 participating French institutions from January 2009 to December 2012 [10]. The Casadei-Gardini study had enrolled 24 patients in several Italian centers [12]. ...
... For the Casadei-Gardini study a whole genome analysis of the primary tumours was performed by the FOUNDATION Cdx technology (F1CDx). A functional enrichment analysis of the mutated genes was carried out with BioPlanet (https://tripod.nih.gov/bioplanet/index.jsp) [12]. ...
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