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  • Hofving, Tobias,1989Gothenburg University,Göteborgs universitet,Institutionen för biomedicin,Sahlgrenska Centrum för Cancerforskning (SCCR),Institute of Biomedicine,Sahlgrenska Center for Cancer Research (SCCR) (author)

SMAD4 haploinsufficiency in small intestinal neuroendocrine tumors

  • Article/chapterEnglish2021

Publisher, publication year, extent ...

  • 2021-01-28
  • Springer Science and Business Media LLC,2021
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:research.chalmers.se:162978dd-9bac-422f-8c4e-f60de3e110ab
  • https://doi.org/10.1186/s12885-021-07786-9DOI
  • https://research.chalmers.se/publication/522219URI
  • https://gup.ub.gu.se/publication/302531URI

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  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • Background: Patients with small intestinal neuroendocrine tumors (SINETs) frequently present with lymph node and liver metastases at the time of diagnosis, but the molecular changes that lead to the progression of these tumors are largely unknown. Sequencing studies have only identified recurrent point mutations at low frequencies with CDKN1B being the most common harboring heterozygous mutations in less than 10% of all tumors. Although SINETs are genetically stable tumors with a low frequency of point mutations and indels, they often harbor recurrent hemizygous copy number alterations (CNAs) yet the functional implications of these CNA are unclear. Methods: Utilizing comparative genomic hybridization (CGH) arrays we analyzed the CNA profile of 131 SINETs from 117 patients. Two tumor suppressor genes and corresponding proteins i.e. SMAD4, and CDKN1B, were further characterized using a tissue microarray (TMA) with 846 SINETs. Immunohistochemistry (IHC) was used to quantify protein expression in TMA samples and this was correlated with chromosome number evaluated with fluorescent in-situ hybridization (FISH). Intestinal tissue from a Smad4+/− mouse model was used to detect entero-endocrine cell hyperplasia with IHC. Results: Analyzing the CGH arrays we found loss of chromosome 18q and SMAD4 in 71% of SINETs and that focal loss of chromosome 12 affecting the CDKN1B was present in 9.4% of SINETs. No homozygous loss of chromosome 18 was detected. Hemizygous loss of SMAD4, but not CDKN1B, significantly correlated with reduced protein levels but hemizygous loss of SMAD4 did not induce entero-endocrine cell hyperplasia in the Smad4+/− mouse model. In addition, patients with low SMAD4 protein expression in primary tumors more often presented with metastatic disease. Conclusions: Hemizygous loss of chromosome 18q and the SMAD4 gene is the most common genetic event in SINETs and our results suggests that this could influence SMAD4 protein expression and spread of metastases. Although SMAD4 haploinsufficiency alone did not induce tumor initiation, loss of chromosome 18 could represent an evolutionary advantage in SINETs explaining the high prevalence of this aberration. Functional consequences of reduced SMAD4 protein levels could hypothetically be a potential mechanism as to why loss of chromosome 18 appears to be clonally selected in SINETs.

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  • Elias, Erik,1979Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery,Sahlgrenska Centrum för Cancerforskning (SCCR),Sahlgrenska Center for Cancer Research (SCCR)(Swepub:gu)xjmaro (author)
  • Rehammar, Anna,1978Gothenburg University,Göteborgs universitet,Institutionen för matematiska vetenskaper,Institutionen för medicin, avdelningen för samhällsmedicin och folkhälsa,Department of Mathematical Sciences,Institute of Medicine, School of Public Health and Community Medicine(Swepub:gu)xlanns (author)
  • Inge, LindaGothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Sahlgrenska Center for Cancer Research (SCCR)(Swepub:gu)xarvli (author)
  • Altiparmak, GülayGothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Sahlgrenska Center for Cancer Research (SCCR)(Swepub:gu)xaltgu (author)
  • Persson, Marta,1979Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Sahlgrenska Center for Cancer Research (SCCR)(Swepub:gu)xwinma (author)
  • Kristiansson, Erik,1978Gothenburg University,Göteborgs universitet,Institutionen för matematiska vetenskaper,Department of Mathematical Sciences(Swepub:gu)xkrier (author)
  • Johansson, Martin E.Göteborgs universitet,University of Gothenburg (author)
  • Nilsson, Ola,1957Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Sahlgrenska Center for Cancer Research (SCCR)(Swepub:gu)xnilol (author)
  • Arvidsson, Yvonne,1960Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för laboratoriemedicin,Sahlgrenska Centrum för Cancerforskning (SCCR),Department of Laboratory Medicine,Sahlgrenska Center for Cancer Research (SCCR)(Swepub:gu)xarvyv (author)
  • Göteborgs universitetInstitutionen för biomedicin (creator_code:org_t)

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  • In:BMC Cancer: Springer Science and Business Media LLC21:11471-2407

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