Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors

Walter, Dirk; Harter, Patrick N.; Battke, Florian; Winkelmann, Ria; Schneider, Markus; Holzer, Katharina; Koch, Christine; Bojunga, Jörg; Zeuzem, Stefan; Hansmann, Martin Leo; Peveling‐Oberhag, Jan; Waidmann, Oliver

doi:10.1038/s41598-018-22115-0

Cited by 42 publications

(38 citation statements)

References 33 publications

(14 reference statements)

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“…Furthermore, despite similar morphology for all primary tumors, metastases exclusively originated from a single lesion in all 5 patients, and where positional data was available (Patients 1 and 2) it can be noted that this tumor was located near the center of the affected intestinal segment. Previous exomebased analyses of paired single intestinal and metastatic samples have yielded puzzling results with a highly varying degree of genetic overlap and in some cases no overlap at all (5,21), and our results thus suggest that a non-metastatic intestinal tumor was sampled when overlap was absent.…”

Section: Discussionmentioning

confidence: 56%

Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine

Elias

Ardalan

Lindberg

et al. 2020

Preprint

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Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several intestinal tumors centered around a regional lymph node metastasis, yet the typical path of evolution of these lesions remains unclear. Here, we determined the complete genome sequences of 37 tumors from 5 patients with multifocal SI-NET, allowing elucidation of phylogenetic relationships between multiple intestinal tumors and metastases in individual patients. Notably, lack of shared somatic mutational events strongly supports that the intestinal tumors were of independent clonal origin. Furthermore, adjacent lymph node metastases arose from a single, typically centrally located, intestinal tumor. Thus, we propose that multifocal SI-NETs form primarily by independent somatic evolution rather than local metastatic spread.

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Section: Discussionmentioning

confidence: 56%

Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine

Elias

Ardalan

Lindberg

et al. 2020

Preprint

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“…In some cases, however, obtaining tumor tissue samples may be difficult due to poor patient condition or a tumor that is difficult to access. Furthermore, recent studies of multi-region NGS analysis revealed intra-and inter-tumor genomic heterogeneities in various types of cancers [47,[81][82][83][84]. The needle biopsy method examines only a tiny fraction of a tumor, potentially influencing the interpretation of NGS assay results.…”

Section: Future Prospects For Msi Testing and Precision Cancer Medicinementioning

confidence: 99%

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

et al. 2019

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Recent innovations in the next-generation sequencing technologies have unveiled that the accumulation of genetic alterations results in the transformation of normal cells into cancer cells. Accurate and timely repair of DNA is, therefore, essential for maintaining genetic stability. Among various DNA repair pathways, the mismatch repair (MMR) pathway plays a pivotal role. MMR deficiency leads to a molecular feature of microsatellite instability (MSI) and predisposes to cancer. Recent studies revealed that MSI-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, regardless of their primary site, have a promising response to immune checkpoint inhibitors (ICIs), leading to the approval of the anti-programmed cell death protein 1 monoclonal antibody pembrolizumab for the treatment of advanced or recurrent MSI-H/dMMR solid tumors that continue to progress after conventional chemotherapies. This new indication marks a paradigm shift in the therapeutic strategy of cancers; however, when considering the optimum indication for ICIs and their safe and effective usage, it is important for clinicians to understand the genetic and immunologic features of each tumor. In this review, we describe the molecular basis of the MMR pathway, diagnostics of MSI status, and the clinical importance of MSI status and the tumor mutation burden in developing therapeutic strategies against gastrointestinal and hepatobiliary malignancies.

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“…The discrepancy in SMAD4 protein expression between tumor sites could i.e. be explained by differing tissue environment conditions and/or genetic intratumoral heterogeneity between primary and metastatic tumors observed in SINETs [ 25 ]. Therefore, further mechanistic studies focused on the effects of disrupted TGFβ-signaling and SINET metastatic capacity could represent a promising future research direction.…”

Section: Discussionmentioning

confidence: 99%

SMAD4 haploinsufficiency in small intestinal neuroendocrine tumors

et al. 2021

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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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Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors

Cited by 42 publications

References 33 publications

Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine

Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

SMAD4 haploinsufficiency in small intestinal neuroendocrine tumors

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