SMAD4 haploinsufficiency in small intestinal neuroendocrine tumors
Journal article, 2021

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.

Chromosome 18

SINET

FISH

Tissue microarray

Haploinsufficiency

SMAD4

Author

Tobias Hofving

University of Gothenburg

Erik Elias

University of Gothenburg

Anna Rehammar

University of Gothenburg

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

Linda Inge

University of Gothenburg

Gülay Altiparmak

University of Gothenburg

Marta Persson

University of Gothenburg

Erik Kristiansson

University of Gothenburg

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

Martin E. Johansson

University of Gothenburg

Ola Nilsson

University of Gothenburg

Yvonne Arvidsson

University of Gothenburg

BMC Cancer

1471-2407 (ISSN)

Vol. 21 1 101

Subject Categories

Medical Genetics

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Genetics

DOI

10.1186/s12885-021-07786-9

PubMed

33509126

More information

Latest update

2/11/2021