Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma

Alexander Quaas, Carina Heydt, Dirk Waldschmidt, Hakan Alakus, Thomas Zander, Tobias Goeser, Philipp Kasper, Christiane Bruns, Anna Brunn, Wilfried Roth, Nils Hartmann, Anne Bunck, Matthias Schmidt, Reinhard Buettner, Sabine Merkelbach-Bruse

Research output: Contribution to journalArticle

Abstract

Background: Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma. Methods: We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2). Results: In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions. Conclusion: Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.

Original languageEnglish (US)
Article number21
JournalBMC Gastroenterology
Volume19
Issue number1
DOIs
StatePublished - Feb 4 2019

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Microsatellite Instability
Carcinoma
Gene Fusion
Microsatellite Repeats
Therapeutics
Hereditary Nonpolyposis Colorectal Neoplasms
High-Throughput Nucleotide Sequencing
Neoplasms
Mutation
DNA Mismatch Repair
Germ-Line Mutation
Paraffin
Formaldehyde
Genes
RNA
DNA
Proteins

Keywords

  • BRCA mutation
  • ERBB2 mutation
  • Microsatellite-instability
  • PARP-inhibition
  • Small bowel adenocarcinoma

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Quaas, A., Heydt, C., Waldschmidt, D., Alakus, H., Zander, T., Goeser, T., ... Merkelbach-Bruse, S. (2019). Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma. BMC Gastroenterology, 19(1), [21]. https://doi.org/10.1186/s12876-019-0942-z

Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma. / Quaas, Alexander; Heydt, Carina; Waldschmidt, Dirk; Alakus, Hakan; Zander, Thomas; Goeser, Tobias; Kasper, Philipp; Bruns, Christiane; Brunn, Anna; Roth, Wilfried; Hartmann, Nils; Bunck, Anne; Schmidt, Matthias; Buettner, Reinhard; Merkelbach-Bruse, Sabine.

In: BMC Gastroenterology, Vol. 19, No. 1, 21, 04.02.2019.

Research output: Contribution to journalArticle

Quaas, A, Heydt, C, Waldschmidt, D, Alakus, H, Zander, T, Goeser, T, Kasper, P, Bruns, C, Brunn, A, Roth, W, Hartmann, N, Bunck, A, Schmidt, M, Buettner, R & Merkelbach-Bruse, S 2019, 'Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma' BMC Gastroenterology, vol. 19, no. 1, 21. https://doi.org/10.1186/s12876-019-0942-z
Quaas, Alexander ; Heydt, Carina ; Waldschmidt, Dirk ; Alakus, Hakan ; Zander, Thomas ; Goeser, Tobias ; Kasper, Philipp ; Bruns, Christiane ; Brunn, Anna ; Roth, Wilfried ; Hartmann, Nils ; Bunck, Anne ; Schmidt, Matthias ; Buettner, Reinhard ; Merkelbach-Bruse, Sabine. / Alterations in ERBB2 and BRCA and microsatellite instability as new personalized treatment options in small bowel carcinoma. In: BMC Gastroenterology. 2019 ; Vol. 19, No. 1.
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AU - Alakus, Hakan

AU - Zander, Thomas

AU - Goeser, Tobias

AU - Kasper, Philipp

AU - Bruns, Christiane

AU - Brunn, Anna

AU - Roth, Wilfried

AU - Hartmann, Nils

AU - Bunck, Anne

AU - Schmidt, Matthias

AU - Buettner, Reinhard

AU - Merkelbach-Bruse, Sabine

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N2 - Background: Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma. Methods: We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2). Results: In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions. Conclusion: Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.

AB - Background: Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma. Methods: We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2). Results: In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions. Conclusion: Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.

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