Differential mutation frequencies in metastatic cutaneous squamous cell carcinomas versus primary tumors

Yilmaz, Ayse Selen; Özer, Hatice Gülçin; Gillespie, J.; Allain, Dawn C.; Bernhardt, Madison N.; Furlan, Karina; Castro, Leticia T. F.; Peters, Sara; Nagarajan, Priyadharsini; Kang, Stephen Y.; Iwenofu, O. Hans; Olencki, Thomas; Teknos, Theodoros N.; Toland, Amanda E.

doi:10.1002/cncr.30459

Cited by 67 publications

(88 citation statements)

References 34 publications

(146 reference statements)

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“…This mutational signature (signature 7) is characteristic of UV-induced mutation and common to almost all UV-associated skin cancers (23). Keratinocyte carcinomas also show a high mutational burden, far exceeding that of other cancers, although the genes mutated vary between BCCs and cSCCs (24,25). Exome sequencing of cSCC shows highest levels of TP53 mutations and loss-of-function CDKN2A mutations.…”

Section: Uv Radiationmentioning

confidence: 99%

“…Exome sequencing of cSCC shows highest levels of TP53 mutations and loss-of-function CDKN2A mutations. Other frequent mutations are found epigenetic regulators such as KMT2C, KMT2D, TET2, and loss-of-function Notch pathway genes such as NOTCH1 and NOTCH2 (24,25). Sequencing studies of metastatic cSCCs reveal higher mutational burden than primary tumors and have associated mutations in KMT2C with poorer outcome, including bone metastases (25,26).…”

Section: Uv Radiationmentioning

confidence: 99%

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Keratinocyte Carcinomas: Current Concepts and Future Research Priorities

Nagarajan

Asgari

Green

et al. 2019

Clinical Cancer Research

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103

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Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are keratinocyte carcinomas, the most frequently diagnosed cancers in fair-skinned populations. Ultraviolet radiation (UVR) is the main driving carcinogen for these tumors, but immunosuppression, pigmentary factors, and aging are also risk factors. Scientific discoveries have improved the understanding of the role of human papillomaviruses (HPV) in cSCC as well as the skin microbiome and a compromised immune system in the development of both cSCC and BCC. Genomic analyses have uncovered genetic risk variants, high-risk susceptibility genes, and somatic events that underlie common pathways important in keratinocyte carcinoma tumorigenesis and tumor characteristics that have enabled development of prediction models for early identification of high-risk individuals. Advances in chemoprevention in high-risk individuals and progress in targeted and immune-based treatment approaches have the potential to decrease the morbidity and mortality associated with these tumors. As the incidence and prevalence of keratinocyte carcinoma continue to increase, strategies for prevention, including effective sun-protective behavior, educational interventions, and reduction of tanning bed access and usage, are essential. Gaps in our knowledge requiring additional research to reduce the high morbidity and costs associated with keratinocyte carcinoma include better understanding of factors leading to more aggressive tumors, the roles of microbiome and HPV infection, prediction of response to therapies including immune checkpoint blockade, and how to tailor both prevention and treatment to individual risk factors and needs.

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Section: Uv Radiationmentioning

confidence: 99%

Section: Uv Radiationmentioning

confidence: 99%

Keratinocyte Carcinomas: Current Concepts and Future Research Priorities

Nagarajan

Asgari

Green

et al. 2019

Clinical Cancer Research

Self Cite

103

123

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show abstract

“…Whole-genome sequencing recently discovered inactivating mutations of a histone modification enzyme, KMT2D (also known as MLL2), in up to 5% of PDAC cases, suggesting its tumor suppression potential 5,9 . Inactivating mutations of KMT2D have also been associated with increased tumorigenesis and metastasis in lymphoma, esophageal, and skin cancers [9][10][11] , further suggesting that it is an important tumorsuppressive gene in cancer. KMT2D is one of the major histone methyltransferases for lysine 4 of histone 3 (H3K4) and mainly mono-and di-methylates H3K4 residue, which are predominant histone marks at distal promoters and enhancers 11,17 .…”

Section: Introductionmentioning

confidence: 99%

“…Inactivating mutations of KMT2D have also been associated with increased tumorigenesis and metastasis in lymphoma, esophageal, and skin cancers [9][10][11] , further suggesting that it is an important tumorsuppressive gene in cancer. KMT2D is one of the major histone methyltransferases for lysine 4 of histone 3 (H3K4) and mainly mono-and di-methylates H3K4 residue, which are predominant histone marks at distal promoters and enhancers 11,17 . Thus, KMT2D is known to play an essential role in establishing active promoter and enhancer landscapes, and cell-specific transcriptome.…”

Section: Introductionmentioning

confidence: 99%

KMT2D links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

Kim

Cao

et al. 2020

Preprint

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Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to posttranscriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a non-canonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the pro-tumoral role of KMT2D. These findings reveal a tumor-suppressive role of KMT2D and identify miR-147b and activin A as novel therapeutic targets in pancreatic cancer.

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“…Mutation profiles of primary tumor versus the metastatic lesion locoregional lymphatic metastasis versus distant metastasis need to be carefully assessed, as often the profiles are not identical. [57][58][59] Similarly, you cannot assume that multiple tumors in the same patient and of the same tumor type will possess the same mutation profile. Second, what criteria are appropriate for defining a positive test result that will then impact clinical management?…”

Section: Technical Issues To Consider For Implementing Somatic Mutatimentioning

confidence: 99%

Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice

Tsongalis

Coleman

2017

The Journal of Clinical Pharma

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Somatic mutation analysis of human cancers has become the standard of practice. Whether screening for single gene variants or sequencing hundreds of cancer-related genes, this genomic information is the basis for precision medicine initiatives in oncology. Genomic profiling results in information that allows oncologists to make a more educated selection of appropriate therapeutic strategies that more often combine traditional cytotoxic chemotherapy and radiation with novel targeted therapies. Here we discuss the nuances of implementing somatic mutation testing in a clinical setting. Keywordsclinical genomics, oncology, precision medicine, pharmacogenomics, somatic mutation Novel therapies, including the use of directed monoclonal antibodies, tyrosine kinase inhibitors, and immunotherapies, have come to fruition as our understanding of the etiology of human cancer expands. From the identification of the first oncogenes and tumor-suppressor genes to current full gene sequencing for the identification of somatic mutations, knowledge of tumor-cell genetic variant profiles has become critical to the management of the cancer patient.1-3 One projection of the Human Genome Project was to gain a more fundamental understanding of human disease at the genomic level such that novel therapeutics could be designed to provide a more personalized approach to disease management. The identification of numerous driver mutations in various human cancers, which are causally implicated in establishing growth advantages to a cell, have also become the target of novel therapies that confer more efficacious outcomes. 4,5 The rapid development of targeted therapies is also resulting in more advanced and focused clinical trial designs whereby testing protocols aim to match patients whose tumors harbor specific somatic mutations with those specific therapies targeting the gene or pathway affected. 6,7 Precision Medicine in OncologyWith respect to the cancer patient, the concept of targeted or individualized therapy can include 2 aspects of what is often termed pharmacogenomics. The first is the more traditional concept that encompasses how an individual may metabolize, absorb, transport, and excrete therapeutic drugs differently based on polymorphisms in the genes that code for these functions. This type of individual variation in metabolism was first described in 510 BC when Pythagoras recognized hemolytic anemia developing in some individuals who consumed fava beans.8 This phenotype was later attributed to a glucose-6-phosphate dehydrogenase deficiency. 9 We have termed pharmacogenomic concepts linked to drug metabolism PGX m , which corresponds to genetic variants that determine drug disposition, also referred to as drug pharmacokinetics.10,11 The conversion of a parent compound to an inactive metabolite or to one that is more easily excreted and the conversion of a prodrug to its active metabolite are examples of PGX m .PGX t is the second aspect of pharmacogenomics that involves the selection of a therapeutic drug based on the...

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Differential mutation frequencies in metastatic cutaneous squamous cell carcinomas versus primary tumors

Cited by 67 publications

References 34 publications

Keratinocyte Carcinomas: Current Concepts and Future Research Priorities

Keratinocyte Carcinomas: Current Concepts and Future Research Priorities

KMT2D links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

Somatic Mutation Analysis of Human Cancers: Challenges in Clinical Practice

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