SNFGE SNFGE
 
Thématique :
- Pancréas/Voies biliaires
Originalité :
Intermédiaire
Solidité :
A confirmer
Doit faire évoluer notre pratique :
Dans certains cas
 
 
Nom du veilleur :
Docteur Marine CAMUS DUBOC
Coup de coeur :
 
 
Gastroenterology
  2019/06  
 
  2019 Jun;156(8):2242-2253.e4.  
  doi: 10.1053/j.gastro.2019.02.037.  
 
  Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers.  
 
  Singhi AD, George B, Greenbowe JR, Chung J, Suh J, Maitra A, Klempner SJ, Hendifar A, Milind JM, Golan T, Brand RE, Zureikat AH, Roy S, Schrock AB, Miller VA, Ross JS, Ali SM, Bahary N  
  https://www.ncbi.nlm.nih.gov/pubmed/30836094  
 
 

Abstract

BACKGROUND & AIMS:

It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations.

METHODS:

We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci.

RESULTS:

KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs.

CONCLUSIONS:

In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.

 

 
Question posée
 
La sélection d’un traitement basé sur les altérations génomiques pour les patients atteints d'adénocarcinomes pancréatiques (PDAC) est limitée. Dans cette étude, des analyses ciblées du profil génomique de 3594 adénocarcinomes du pancréas ont été réalisées.
 
Question posée
 
17% des adénocarcinomes pancréatiques portent des modifications susceptibles d'être ciblées par les traitements anticancéreux actuellement disponibles, tels que les gènes de fusion, les délétions intragéniques, l'instabilité des microsatellites et la charge de mutation tumorale élevée.
 
Commentaires

Cette étude fournit un condensé d'altérations génomiques connues dans l’adénocarcinome pancréatique pouvant servir de ressource clinique pour orienter le traitement futur des patients en fonction du profil génomique ciblé.

Cependant cette étude est rétrospective par conception, et la véritable utilité clinique d’une altération génomique particulière, y compris la charge mutationnelle de la tumeur, est inconnue jusqu’à la réalisation d’un essai clinique prospectif.

 
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