DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway

Adam, Liana; Lucas, F. Anthony San; Fowler, Richard; Yu, Yao; Wu, Wenhui; Liu, Yu-Lun; Wang, Huamin; Menter, David G.; Tetzlaff, Michael T.; Ensor, Joe; Manyam, Ganiraju C.; Arold, Stefan T.; Huff, Chad; Kopetz, Scott; Scheet, Paul; Overman, Michael J.

doi:10.1158/1078-0432.ccr-18-1480

Cited by 24 publications

(45 citation statements)

References 43 publications

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“…By contrast, genetic analyses of SBAs, including nonampullary DAs, have been performed by multiple groups [17][18][19][20][21][22][23]. Schrock et al [20] analyzed mutations of cancer-related genes in 317 SBA samples and showed that the genetic signatures of SBAs were distinct from those in CRCs or gastric cancers.…”

Section: Introductionmentioning

confidence: 99%

Integrated genetic and epigenetic analysis of cancer‐related genes in non‐ampullary duodenal adenomas and intramucosal adenocarcinomas

Ota

Sawada

Tsuyama

et al. 2020

The Journal of Pathology

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The molecular and clinical characteristics of non-ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer-related genes in these lesions. One hundred and seven non-ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal-type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric-type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and MLH1. Then using next-generation sequencing, we performed targeted exome sequence analysis within 75 cancer-related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal-and gastric-type tumors, which suggests the presence of at least two separate carcinogenic pathways in non-ampullary duodenal adenocarcinomas. The prevalence of CIMP-positive lesions was higher in intramucosal adenocarcinomas than in adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non-ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that APC was the most frequently mutated gene in these lesions (56/102; 55%), followed by KRAS (13/102; 13%), LRP1B (10/102; 10%), GNAS (8/102; 8%), ERBB3 (7/102; 7%), and RNF43 (6/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear β-catenin accumulation (87/102; 85%) as well as mutations of WNT pathway components (60/102; 59%) indicates the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of APC gene mutations in small bowel adenocarcinomas as well as the difference in the APC mutation distributions between small intestinal-type adenomas and intramucosal adenocarcinomas may indicate that the adenoma-carcinoma sequence has only limited involvement in duodenal carcinogenesis.

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Section: Introductionmentioning

confidence: 99%

Integrated genetic and epigenetic analysis of cancer‐related genes in non‐ampullary duodenal adenomas and intramucosal adenocarcinomas

Ota

Sawada

Tsuyama

et al. 2020

The Journal of Pathology

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“…It is generally believed that dysregulated ERBB2 signaling plays a key role in the development of pancreatic cancer (Lin et al, 2019). For the treatment of intestinal adenocarcinoma, ERBB2 mutations and amplification in small intestinal adenocarcinoma patients also make a great contribution (Adam et al, 2019). Recent studies have shown that HER2 targeted therapy has significantly improved outcomes in patients with breast and stomach problems with ERBB2 mutation/amplification (Meric-Bernstam et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Sparse Graph Regularization Non-Negative Matrix Factorization Based on Huber Loss Model for Cancer Data Analysis

Wang

Liu

et al. 2019

Front. Genet.

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Non-negative matrix factorization (NMF) is a matrix decomposition method based on the square loss function. To exploit cancer information, cancer gene expression data often uses the NMF method to reduce dimensionality. Gene expression data usually have some noise and outliers, while the original NMF loss function is very sensitive to non-Gaussian noise. To improve the robustness and clustering performance of the algorithm, we propose a sparse graph regularization NMF based on Huber loss model for cancer data analysis (Huber-SGNMF). Huber loss is a function between L 1-norm and L 2-norm that can effectively handle non-Gaussian noise and outliers. Taking into account the sparsity matrix and data geometry information, sparse penalty and graph regularization terms are introduced into the model to enhance matrix sparsity and capture data manifold structure. Before the experiment, we first analyzed the robustness of Huber-SGNMF and other models. Experiments on The Cancer Genome Atlas (TCGA) data have shown that Huber-SGNMF performs better than other most advanced methods in sample clustering and differentially expressed gene selection.

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“…Notably, the mutation rate of APC is markedly higher in CRC than in small intestine adenocarcinoma [ 148 ]. Nevertheless, some inactive variants of Wnt repressors RNF43 and ZNRF3 could lead to the activation of this pathway in other intestinal tumors [ 187 ].…”

Section: Balance Between Pro-apoptotic and Pro-survival Factors (Mmentioning

confidence: 99%

Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment

Marin

Macı́as

Monte

et al. 2020

Cancers

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The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).

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DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway

Cited by 24 publications

References 43 publications

Integrated genetic and epigenetic analysis of cancer‐related genes in non‐ampullary duodenal adenomas and intramucosal adenocarcinomas

Integrated genetic and epigenetic analysis of cancer‐related genes in non‐ampullary duodenal adenomas and intramucosal adenocarcinomas

Sparse Graph Regularization Non-Negative Matrix Factorization Based on Huber Loss Model for Cancer Data Analysis

Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment

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