Genetic and biological hallmarks of colorectal cancer

Li, Jiexi; Ma, Xingdi; Chakravarti, Deepavali; Shalapour, Shabnam; DePinho, Ronald A.

doi:10.1101/gad.348226.120

Cited by 282 publications

(168 citation statements)

References 417 publications

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“…Similarly, in colorectal cancer the identification of somatic mutations suggests a complex scenario where PTPRG can be modified quantitatively (reduced expression driven by methylation/non-coding RNAs) and qualitatively (somatic mutations), a feature shared with the alteration of other classic TSGs in cancer development. ( Capellini et al, 2021 ; Li et al, 2021 ). The case of Merkel Cell carcinoma is noteworthy, where integration of Merkel cell polyomavirus (MCV or MCPyV) to form different length fusions with intron 1 of the human PTPRG gene.…”

Section: Ptprg Interacts With Characteristic Oncogenes In Specific Cancer Typesmentioning

confidence: 99%

The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

Böni

Sorio

2022

Front. Cell Dev. Biol.

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Members of the Protein Tyrosine Phosphatase (PTPs) family are associated with growth regulation and cancer development. Acting as natural counterpart of tyrosine kinases (TKs), mainly involved in crucial signaling pathways such as regulation of cell cycle, proliferation, invasion and angiogenesis, they represent key parts of complex physiological homeostatic mechanisms. Protein tyrosine phosphatase gamma (PTPRG) is classified as a R5 of the receptor type (RPTPs) subfamily and is broadly expressed in various isoforms in different tissues. PTPRG is considered a tumor-suppressor gene (TSG) mapped on chromosome 3p14-21, a region frequently subject to loss of heterozygosity in various tumors. However, reported mechanisms of PTPRG downregulation include missense mutations, ncRNA gene regulation and epigenetic silencing by hypermethylation of CpG sites on promoter region causing loss of function of the gene product. Inactive forms or total loss of PTPRG protein have been described in sporadic and Lynch syndrome colorectal cancer, nasopharyngeal carcinoma, ovarian, breast, and lung cancers, gastric cancer or diseases affecting the hematopoietic compartment as Lymphoma and Leukemia. Noteworthy, in Central Nervous System (CNS) PTPRZ/PTPRG appears to be crucial in maintaining glioblastoma cell-related neuronal stemness, carving out a pathological functional role also in this tissue. In this review, we will summarize the current knowledge on the role of PTPRG in various human cancers.

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Section: Ptprg Interacts With Characteristic Oncogenes In Specific Cancer Typesmentioning

confidence: 99%

The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

Böni

Sorio

2022

Front. Cell Dev. Biol.

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“…Despite decades-long marker discovery efforts, currently dominated by larger-scale genomics and proteomics initiatives (reviewed in [ 54 , 55 , 56 , 57 ]), only a few molecular biomarkers of CRC are currently known and even fewer are clinically approved for medical use (reviewed in [ 6 ]) Traditional ‘omics’ technologies are perfectly capable of mechanistic sifting through tens of thousands of expressed genes and are routinely employed to find transcripts or proteins with altered expression patterns correlating with the disease in question. We aimed to explore a more rational approach to disease marker discovery.…”

Section: Discussionmentioning

confidence: 99%

Bottom-Up Approach to the Discovery of Clinically Relevant Biomarker Genes: The Case of Colorectal Cancer

Kamel

Schneider

Nisar

et al. 2022

Cancers

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Traditional approaches to genome-wide marker discovery often follow a common top-down strategy, where a large scale ‘omics’ investigation is followed by the analysis of functional pathways involved, to narrow down the list of identified putative biomarkers, and to deconvolute gene expression networks, or to obtain an insight into genetic alterations observed in cancer. We set out to investigate whether a reverse approach would allow full or partial reconstruction of the transcriptional programs and biological pathways specific to a given cancer and whether the full or substantially expanded list of putative markers could thus be identified by starting with the partial knowledge of a few disease-specific markers. To this end, we used 10 well-documented differentially expressed markers of colorectal cancer (CRC), analyzed their transcription factor networks and biological pathways, and predicted the existence of 193 new putative markers. Incredibly, the use of a validation marker set of 10 other completely different known CRC markers and the same procedure resulted in a very similar set of 143 predicted markers. Of these, 138 were identical to those found using the training set, confirming our main hypothesis that a much-expanded set of disease markers can be predicted by starting with just a small subset of validated markers. Further to this, we validated the expression of 42 out of 138 top-ranked predicted markers experimentally using qPCR in surgically removed CRC tissues. We showed that 41 out of 42 mRNAs tested have significantly altered levels of mRNA expression in surgically excised CRC tissues. Of the markers tested, 36 have been reported to be associated with aspects of CRC in the past, whilst only limited published evidence exists for another three genes (BCL2, PDGFRB and TSC2), and no published evidence directly linking genes to CRC was found for CCNA1, SHC1 and TGFB3. Whilst we used CRC to test and validate our marker discovery strategy, the reported procedures apply more generally to cancer marker discovery.

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“…Previous studies in different types of cancer have demonstrated the critical roles of stromal cells in the tumor microenvironment in regulating cancer cell functions [31][32][33][34] . Moreover, studies from our group and others suggested that ECs, a critical but understudied component of the microenvironment, promoted cell survival in CRC and few other types of cancer by secreting paracrine factors (angiocrine) 12,28,35,36 .…”

Section: Discussionmentioning

confidence: 99%

Liver endothelium promotes HER3-mediated cell survival in KRAS wild-type and mutant colorectal cancer cells

Rathore

Wright

Bhattacharya

et al. 2021

Preprint

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We previously showed that human epidermal growth factor receptor 3 (HER3, also known as ERBB3) is a key mediator in liver endothelial cell (EC) promoting colorectal cancer (CRC) growth and chemoresistance, and suggested HER3-targeted therapy as a strategy for treating patients with metastatic CRC (mCRC) in the liver. Meanwhile, KRAS mutations occur in 40–50% of mCRC and render CRC resistant to therapies targeting the other HER family protein epidermal growth factor receptor (EGFR). It is necessary to elucidate the roles of KRAS mutation status in HER3-mediated cell survival and CRC response to HER3 inhibition. In the present study, we demonstrated that liver EC-secreted factors activated HER3 and promoted cell survival in KRAS wild-type and mutant CRC cells and tumors, and that blocking HER3 with an antibody, seribantumab, blocked EC-induced CRC survival. Our findings highlight a potential of utilizing HER3-targeted therapies for treating patients with mCRC regardless of KRAS mutation status.

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Genetic and biological hallmarks of colorectal cancer

Cited by 282 publications

References 417 publications

The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

The Role of the Tumor Suppressor Gene Protein Tyrosine Phosphatase Gamma in Cancer

Bottom-Up Approach to the Discovery of Clinically Relevant Biomarker Genes: The Case of Colorectal Cancer

Liver endothelium promotes HER3-mediated cell survival in KRAS wild-type and mutant colorectal cancer cells

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