Personalized Oncogenomics in the Management of Gastrointestinal Carcinomas—Early Experiences from a Pilot Study

Sheffield, Brandon S.; Tessier‐Cloutier, Basile; Li-Chang, Hector; Shen, Yaoqing; Pleasance, Erin; Kasaian, Katayoon; Li, Y; Jones, Steven J.M.; Lim, Howard John; Renouf, Daniel J.; Huntsman, David G.; Yip, Stephen; Laskin, Janessa; Marra, Marco A.; Schaeffer, David F.

doi:10.3747/co.23.3165

Cited by 9 publications

(12 citation statements)

References 29 publications

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“…The study of genetic and epigenetic alterations mediating the molecular alterations and the malignant transformation of biliary cells occurring in CC may foster novel diagnostic, prognostic and therapeutic approaches (13). Developing interest in the molecular medicine and molecular genetics in the context of personalized, preventive, predictive and participatory medicine to provide better medical care in order to decrease the incidence and prevalence of the disease, as well as the study of the epigenetic alterations for the identification of genes involved in the tumorigenesis may prove to be beneficial (14). Since epigenetic alterations in gene expression are associated with CC, genes that are differentially methylated in CC may be useful in providing valuable information on potential markers for the detection of early-stage curable disease, markers prognostic of response to specific treatments and overall prognosis and novel targets for the design of rational therapies (4,6).…”

Section: Diagnostic Snagsmentioning

confidence: 99%

“…Tissue heterogeneity in carcinomas confers a significant problem in early diagnosis. Although single-gene predictive assays are available, there is a need for the analysis of multiple gene loci, since the genetic, proteomic and miRNA content may vary in the biopsied sample due to tissue heterogeneity (14,49). Whole-genome sequencing and RNA sequencing may provide a comprehensive analysis of the somatic mutations and gene expression, and provide novel insights on the use of genomic data for the treatment of individual patients (14).…”

Section: Diagnostic Developmentmentioning

confidence: 99%

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The promising role of epigenetic mediators and microRNAs in the early diagnosis of cholangiocarcinoma (Review)

2019

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Cholangiocarcinoma (CC) is a highly lethal malignant tumor which arises from the biliary tract epithelium and is notoriously difficult to diagnose. Common risk factors for CC are primary sclerosing cholangitis, liver fluke infestation and hepatolithiasis. Although CCs are relatively uncommon tumors, the worldwide rising incidences and mortality rate for intrahepatic CC (ICC) renders it a disease of interest for research. CCs are usually fatal due to the typically late clinical presentation and the lack of effective non-surgical therapeutic modalities. The overall survival rate, including following tumor resection, is poor with <5% of patients surviving 5 years and this rate has not significantly improved over the past 30 years. Thus, there is a need to diagnose CC at an early stage, and advances in immunohistochemistry, molecular genetics, pharmacogenomics and personalized medicine may aid in the study of the pathological basis of CC at the gene and protein level. Understanding the genetic and proteomic alterations in CC would not only increase the therapeutic efficacy, but would also provide a better treatment strategy. Epigenetic alterations that induce gene expression in cancers have been well established. Among the epigenetic mechanisms, targeting DNA hypermethylation and histone deacetylation with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors has been reported in a number of cancer types. In CC, targeting the epigenetic pathways appears to be a promising approach for treatment. This review aims to provide a comprehensive overview of the putative role of epigenetic alterations and proteomic alterations in CC. Furthermore, the role of these alterations in early diagnosis, as prognostic markers, and therapeutics for better treatment strategies will be highlighted. Contents 1. Introduction 2. Diagnostic snags 3. Mechanism of tumorigenesis 4. Epigenetic alterations in cholangiocarcinoma 5. Diagnostic development 6. Epigenetic therapy of cancer 7. Conclusions

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Section: Diagnostic Snagsmentioning

confidence: 99%

Section: Diagnostic Developmentmentioning

confidence: 99%

The promising role of epigenetic mediators and microRNAs in the early diagnosis of cholangiocarcinoma (Review)

2019

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“…The mother’s wishes may evolve over time as the child grows older, mom’s own medical situation changes, and science yields novel insights and diagnostic and therapeutic possibilities, such as with personalized onco-genomics. 23 …”

Section: The Casementioning

confidence: 99%

Please Test My Child for a Cancer Gene, but Don’t Tell Her

2018

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A 38 year old woman is diagnosed with Li-Fraumeni syndrome, an autosomal dominant genetic condition that predisposes to a variety of cancers. The woman has an 11-year-old daughter named Karen. The geneticist recommends that the child be tested for the Li-Fraumeni genetic variant. The mother is very concerned about the impact of testing and diagnosis on Karen’s psychological well-being. She describes Karen as “highly strung” and as “a worrier.” The child has been diagnosed with an anxiety disorder, and is followed by a psychologist for counseling. The child is otherwise well. The mother requests that testing be done without disclosing it to the child by adding the test on to routine blood work done for another reason and the results only revealed if they are positive. Experts in genetics, law, and bioethics discuss whether it is permissible to test the child without her knowledge or assent.

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“…Biopsies of the liver lesion and a vertebral lesion revealed moderately differentiated adenocarcinoma, but no site-specific immunohistochemical profile. NGS demonstrated the IDH1 R132C somatic mutation, and the patient was treated with gemcitabine and cisplatin for metastatic BTC [25].…”

Section: Functional and Clinical Significance Of The Specific Mutatiomentioning

confidence: 99%

A Case of Metastatic Biliary Tract Cancer Diagnosed Through Identification of an IDH1 Mutation

2018

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The role of next‐generation sequencing from either circulating tumor DNA (ctDNA) or formalin‐fixed paraffin‐embedded (FFPE) tissue to identify therapeutically targetable genomic alterations has been well established. Genomic profiling may also have untapped potential as a diagnostic tool in cases in which traditional immunohistochemistry assays cannot establish a clear histologic diagnosis. Expanding the number of histologies with unique genomic signatures or alterations is critical in this setting. Here we describe a case of a 73‐year‐old man who presented with a duodenal mass extending to the liver and peritoneal carcinomatosis, initially thought to be metastatic duodenal adenocarcinoma. Subsequent genomic profiling of ctDNA and FFPE tissue revealed an IDH1 mutation, which is rare in duodenal adenocarcinoma but common in biliary tract cancers (BTCs). This finding prompted a second biopsy, which revealed pancreaticobiliary adenocarcinoma. The clinical significance of IDH mutations in terms of their molecular specificity to certain histologies is reviewed. Recent and ongoing investigations into IDH inhibitors for advanced and metastatic BTCs are also discussed. Key Points This case demonstrates a novel use of next‐generation sequencing as a diagnostic tool to modify a primary cancer diagnosis, leading to important changes in therapy. Isocitrate dehydrogenase mutations are rare in solid organ malignancies and are highly specific for biliary tract cancers (BTCs) within the gastrointestinal malignancies. IDH inhibition is an active area of investigation in metastatic BTCs; early results have been promising.

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Personalized Oncogenomics in the Management of Gastrointestinal Carcinomas—Early Experiences from a Pilot Study

Abstract: Background Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic

Cited by 9 publications

References 29 publications

The promising role of epigenetic mediators and microRNAs in the early diagnosis of cholangiocarcinoma (Review)

The promising role of epigenetic mediators and microRNAs in the early diagnosis of cholangiocarcinoma (Review)

Please Test My Child for a Cancer Gene, but Don’t Tell Her

A Case of Metastatic Biliary Tract Cancer Diagnosed Through Identification of an IDH1 Mutation

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