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

ABSTRACT: Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease.Because it is difficult to predict which cSCCs are more likely to metastasize, and because to the best of the authors' knowledge there are no targeted therapies specifically designated for patients with metastatic cSCC, exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs was performed to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit. The authors compared their results with published sequencing results of an additional 223 primary tumors and 68 metastatic cSCCs.The authors identified genes demonstrating higher mutation frequencies in metastatic cSCC compared with primary tumors, including the chromatin remodeling gene lysine methyltransferase 2D (KMT2D) and the classic skin tumor suppressor tumor protein p53 (TP53), which was found to be mutated in 54% of primary tumors compared with 85% of metastatic tumors (P<.0001).These studies appear to uncover potential pathways that are important in metastatic cSCC and that broaden understanding of the biology contributing to aggressive tumor behavior. These results may lead to new therapeutic strategies. Cancer 2017;123:1184-1193. © 2016 American Cancer Society.

SUBMITTER: Yilmaz AS

PROVIDER: S-EPMC5360561 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Yilmaz Ayse Selen AS Ozer Hatice Gulcin HG Gillespie Jessica L JL Allain Dawn C DC Bernhardt Madison N MN Furlan Karina Colossi KC Castro Leticia T F LT Peters Sara B SB Nagarajan Priyadharsini P Kang Stephen Y SY Iwenofu O Hans OH Olencki Thomas T Teknos Theodoros N TN Toland Amanda Ewart AE

Cancer 20161201 7

<h4>Background</h4>Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease.<h4>Methods</h4>Because it is difficult to predict which cSCCs are more likely to metastas ...[more]

PMID: 27906449

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Project description:UnlabelledBackgroundCilia are essential organelles in multiple organ systems, including the kidney where they serve as important regulators of renal homeostasis. Renal nephron cilia emanate from the apical membrane of epithelia, extending into the lumen where they function in flow-sensing and ligand-dependent signaling cascades. Ciliary dysfunction underlies renal cyst formation that is in part caused by deregulation of planar cell polarity and canonical Wnt signaling. Renal cancer pathologies occur sporadically or in heritable syndromes caused by germline mutations in tumor suppressor genes including VHL. Importantly, Von Hippel-Lindau (VHL) patients frequently develop complex renal cysts that can be considered a premalignant stage. One of the well-characterized molecular functions of VHL is its requirement for the maintenance of cilia. In this study, tissue from 110 renal cancer patients who underwent nephrectomy was analyzed to determine if lower ciliary frequency is a common hallmark of renal tumorigenesis by comparing cilia frequencies in both tumor and adjacent parenchymal tissue biopsies from the same kidney.MethodsWe stained sections of human renal material using markers for cilia. Preliminary staining was performed using an immunofluorescent approach and a combination of acetylated-?-tubulin and pericentrin antibodies and DAPI. After validation of an alternative, higher throughput approach using acetylated-?-tubulin immunohistochemistry, we continued to manually quantify cilia in all tissues. Nuclei were separately counted in an automated fashion in order to determine ciliary frequencies. Similar staining and scoring for Ki67 positive cells was performed to exclude that proliferation obscures cilia formation potential.ResultsSamples from renal cell carcinoma patients deposited in our hospital tissue bank were previously used to compose a tissue microarray containing three cores of both tumor and parenchymal tissue per patient. Cilia frequencies in a total of eighty-nine clear cell, eight papillary, five chromophobe renal cell carcinomas, two sarcomatoid renal tumors and six oncocytomas were determined. A marked decrease of primary cilia across renal cell carcinoma subtypes was observed compared to adjacent nontumorigenic tissue.ConclusionsOur study shows that cilia are predominantly lost in renal cell carcinomas compared to tissue of the tumor parenchyma. These results suggest that ciliary loss is common in renal tumorigenesis, possibly participating in the sequence of cellular events leading to malignant tumor development. Future therapies aimed at restoring or circumventing cilia signaling might therefore aid in current treatment efficacy.

Dataset Information

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

Publications

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

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