Targeted mutational analysis of inflammatory bowel disease–associated colorectal cancers

Alpert, Lindsay; Yassan, Lindsay; Poon, Rachel; Kadri, Sabah; Niu, Nifang; Patil, Sachin; Mujacic, Ibro; Montes, David M.; Galbo, Filippo; Wurst, Michelle N.; Zhen, Chao Jie; Cohen, Russell D.; Rubin, David T.; Pekow, Joel; Weber, Christopher R.; Xiao, Shu‐Yuan; Hart, John; Segal, Jeremy P.; Setia, Namrata

doi:10.1016/j.humpath.2019.04.013

Cited by 21 publications

(19 citation statements)

References 15 publications

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“…Molecular profiling of 428 patients with advanced CRC revealed a IDH1 mutation rate of 0.9% [ 133 ]. More recent studies observed IDH1 mutations in 7% of inflammatory bowel disease-associated (IBD) CRC [ 134 ] and 11% of colitis-associated CRC [ 135 ], compared to 1% of sporadic CRC, providing a therapeutic target in these types of CRC tumors.…”

Section: Mitochondrial Metabolism Of Colorectal Cancermentioning

confidence: 99%

“…A handful of studies with AG-881 for treating glioblastomas and hematopoietic malignancies peaked with a Phase III trial in glioblastoma patients in the beginning of 2020. In the future, IDH inhibitors might provide an additional therapeutic option for the treatment of IBD-associated CRC, which exhibit a IDH 1 mutation rate of 7% (IBD-associated CRC) and 11% (colitis-associated CRC), respectively [ 134 , 135 ].…”

Section: Cancer Specific Mitochondrial Metabolism As a Therapeuticmentioning

confidence: 99%

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Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Neitzel

Demuth

Wittmann

et al. 2020

Cancers

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Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

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Section: Mitochondrial Metabolism Of Colorectal Cancermentioning

confidence: 99%

Section: Cancer Specific Mitochondrial Metabolism As a Therapeuticmentioning

confidence: 99%

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Neitzel

Demuth

Wittmann

et al. 2020

Cancers

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“…In this review, we reported all the studies about genetic and molecular alterations described in human IBD-CRC. Three studies have investigated the genetic alterations in IBD-CRC using high-throughput sequencing technologies, 5,8,9 the results of which support the theory that most IBD-CRCs arise through different pathways than S-CRC. They have also expanded existing knowledge of the molecular alterations in IBD-CRC, especially the identification of potentially targetable mutations and some relevant recurrent alterations (MYC amplification, IDH1, FBXW7), even though most of these findings did not reach statistical significance.…”

Section: Discussionmentioning

confidence: 85%

“…Three studies have explored the genomic features of IBD-CRC through high-throughput sequencing. 5,8,9 In a first study, 5 next-generation sequencing was used to investigate coding sequence alterations in 315 cancer-related genes in 47 IBD-CRC samples and compare them with S-CRC alterations reported in The Cancer Genome Atlas (TCGA). Approximately six genetic alterations per tumor were identified for IBD-CRC; among these, three genes were recurrently altered (!…”

Section: Genomics In Ibd-crcmentioning

confidence: 99%

“…8 More recently, 55 tumors from 48 IBD-CRC patients (35 tumors from 30 UC patients, 18 from 16 CD patients, two from patients with indeterminate colitis) were studied through a 50 gene hot-spot solid tumor panel. 9 IBD-CRC tumor genomic profiles were compared with S-CRC TCGA data. Similar results were found to the previous genomic studies, including the presence of IDH1 mutations in a subset of IBD-CRC (7% in IBD-CRC versus 1% in S-CRC from TCGA, with difference reaching statistical significance).…”

Section: Genomics In Ibd-crcmentioning

confidence: 99%

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Genomic and molecular alterations in human inflammatory bowel disease‐associated colorectal cancer

et al. 2020

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Patients with inflammatory bowel disease are at increased risk of colorectal cancer, which has worse prognosis than sporadic colorectal cancer. Until recently, understanding of pathogenesis in inflammatory bowel disease-associated colorectal cancer was restricted to the demonstration of chromosomic/microsatellite instabilities and aneuploidy. The advance of high-throughput sequencing technologies has highlighted the complexity of the pathobiology and revealed recurrently mutated genes involved in the RTK/RAS, PI3K, WNT, and TGFβ pathways, leading to potentially new targetable mutations. Moreover, alterations of mitochondrial DNA and the dysregulation of non-coding sequences have also been described, as well as several epigenetic modifications. Although recent studies have brought new insights into pathobiology and raised the prospect of innovative therapeutic approaches, the understanding of colorectal carcinogenesis in inflammatory bowel disease and how it differs from sporadic colorectal cancer remains not fully elucidated. Further studies are required to better understand the pathogenesis and molecular alterations leading to human inflammatory bowel disease-associated colorectal cancer.

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Animal Model of Inflammatory Bowel Disease Leading to Cancer and Role of Genetic Variation in Colitis-Associated Cancer

Thangaraj

Ramalingam

Paul

2022

Handbook of Animal Models and Its Uses in Cancer Research

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Targeted mutational analysis of inflammatory bowel disease–associated colorectal cancers

Cited by 21 publications

References 15 publications

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Genomic and molecular alterations in human inflammatory bowel disease‐associated colorectal cancer

Animal Model of Inflammatory Bowel Disease Leading to Cancer and Role of Genetic Variation in Colitis-Associated Cancer

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