title: ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma.
abstract: OBJECTIVE
  Small bowel adenocarcinoma (SBA) is a rare and aggressive tumour with poor outcomes. Because of its low incidence, the number prospective studies remains insufficient leading to poor knowledge and absence of standard of care. Aiming to better understand small bowel carcinogenesis we investigated the frequency of somatic mutations in a large data set of patients in more than 740 mutational hotspots among 46 genes.
  
  
  METHODS
  In total, 83 SBA cases were selected from two European databases. The sequencing was performed using the Ion 316 Chip. Additionally we looked into ERBB2 expression and microsatellite instability (MSI) status.
  
  
  RESULTS
  The tumours most frequently were duodenal (47%) and stage ⩾3 (63%). Eight genes were mutated with a frequency >5%: KRAS, TP53, APC, SMAD4, PIK3CA, ERBB2, BRAF and FBXW7. ERBB2 alterations are present in 10 patients (12%) through mutations (7 cases) or amplifications (3 cases). ERBB2 mutations were significantly associated with duodenal tumour location (P=0.04). In this group, there was a positive association with dMMR status (P=0.006) and APC mutation (P=0.02) but negative association with p53 mutations (P=0.038).
  
  
  CONCLUSIONS
  This study describes the first large screening of somatic mutations in SBA using next generation sequencing. The ERBB2 mutation was revealed to be one of the most frequent alterations in SBA with a distribution dependent on tumour location. In most cases ERBB2 mutation was identical (p.L755S). In clinical practice, this may suggest that more than 10% of the patients with SBA could be treated using an anti-ERBB2-targeted agent.
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
authors.forename: Anais
authors.initials: A
authors.lastname: Laforest
authors.affiliation: Gastroenterology and Digestive Oncology, CHU Avicenne, HUPSSD, APHP, University Paris 13, Bobigny, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Aparicio
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
authors.forename: Aziz
authors.initials: A
authors.lastname: Zaanan
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
authors.forename: Fabio Pittella
authors.initials: FP
authors.lastname: Silva
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Didelot
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Desbeaux
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Le Corre
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
authors.forename: Leonor
authors.initials: L
authors.lastname: Benhaim
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Pallier
authors.affiliation: Department of Pathology, University Hospital Carl Gustav Carus at the TU Dresden, Dresden, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Aust
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus at the TU Dresden, Dresden, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Pistorius
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blons
authors.affiliation: Department of Pathology, Hopital Saint-Antoine, Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Svrcek
authors.affiliation: Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France. Electronic address: pierre.laurent-puig@parisdescartes.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016009:Chi-Square Distribution; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D005060:Europe; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007414:Intestinal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D007421:Intestine, Small / Q000201:enzymology / Q000473:pathology; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C555337:APC protein, human; C495901:TP53 protein, human; C508053:ERBB2 protein, human
keywords: ERBB2; Mutations; Sequencing; Small intestine cancer