Anais Laforest1, Thomas Aparicio2, Aziz Zaanan1, Fabio Pittella Silva1, Audrey Didelot1, Aurélien Desbeaux1, Delphine Le Corre1, Leonor Benhaim1, Karine Pallier1, Daniela Aust3, Steffen Pistorius4, Hélène Blons1, Magali Svrcek5, Pierre Laurent-Puig6. 1. Université Paris Descartes, Sorbone Paris Cité, Paris, France; Inserm UMR-S775 Bases Moléculaires de la réponse aux xénobiotiques, Paris, France. 2. Gastroenterology and Digestive Oncology, CHU Avicenne, HUPSSD, APHP, University Paris 13, Bobigny, France. 3. Department of Pathology, University Hospital Carl Gustav Carus at the TU Dresden, Dresden, Germany. 4. Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus at the TU Dresden, Dresden, Germany. 5. Department of Pathology, Hopital Saint-Antoine, Paris, France. 6. 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.
Abstract
AIM OF THE STUDY: 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.
AIM OF THE STUDY: 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: Liana Adam; F Anthony San Lucas; Richard Fowler; Yao Yu; Wenhui Wu; Yulun Liu; Huamin Wang; David Menter; Michael T Tetzlaff; Joe Ensor; Ganiraju Manyam; Stefan T Arold; Chad Huff; Scott Kopetz; Paul Scheet; Michael J Overman Journal: Clin Cancer Res Date: 2018-10-23 Impact factor: 12.531
Authors: Alexa B Schrock; Craig E Devoe; Robert McWilliams; James Sun; Thomas Aparicio; Philip J Stephens; Jeffrey S Ross; Richard Wilson; Vincent A Miller; Siraj M Ali; Michael J Overman Journal: JAMA Oncol Date: 2017-11-01 Impact factor: 31.777