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A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-? Superfamily.

ABSTRACT: We present an integromic analysis of gene alterations that modulate transforming growth factor ? (TGF-?)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-? signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-? ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-? superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-? signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-? superfamily.

SUBMITTER: Korkut A

PROVIDER: S-EPMC6370347 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily.

Korkut Anil A Zaidi Sobia S Kanchi Rupa S RS Rao Shuyun S Gough Nancy R NR Schultz Andre A Li Xubin X Lorenzi Philip L PL Berger Ashton C AC Robertson Gordon G Kwong Lawrence N LN Datto Mike M Roszik Jason J Ling Shiyun S Ravikumar Visweswaran V Manyam Ganiraju G Rao Arvind A Shelley Simon S Liu Yuexin Y Ju Zhenlin Z Hansel Donna D de Velasco Guillermo G Pennathur Arjun A Andersen Jesper B JB O'Rourke Colm J CJ Ohshiro Kazufumi K Jogunoori Wilma W Nguyen Bao-Ngoc BN Li Shulin S Osmanbeyoglu Hatice U HU Ajani Jaffer A JA Mani Sendurai A SA Houseman Andres A Wiznerowicz Maciej M Chen Jian J Gu Shoujun S Ma Wencai W Zhang Jiexin J Tong Pan P Cherniack Andrew D AD Deng Chuxia C Resar Linda L Weinstein John N JN Mishra Lopa L Akbani Rehan R

Cell systems 20180926 4

We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encod ...[more]

PMID: 30268436

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Project description:PURPOSE:This study examined targeted genomic variants of transforming growth factor beta (TGFB) signaling in Appalachian women. Appalachian women with cervical cancer were compared to healthy Appalachian counterparts to determine whether these polymorphic alleles were over-represented within this high-risk cancer population, and whether lifestyle or environmental factors modified the aggregate genetic risk in these Appalachian women. METHODS:Appalachian women's survey data and blood samples from the Community Awareness, Resources, and Education (CARE) CARE I and CARE II studies (n?=?163 invasive cervical cancer cases, 842 controls) were used to assess gene-environment interactions and cancer risk. Polymorphic allele frequencies and socio-behavioral demographic measurements were compared using t tests and ?2 tests. Multivariable logistic regression was used to evaluate interaction effects between genomic variance and demographic, behavioral, and environmental characteristics. RESULTS:Several alleles demonstrated significant interaction with smoking (TP53 rs1042522, TGFB1 rs1800469), alcohol consumption (NQO1 rs1800566), and sexual intercourse before the age of 18 (TGFBR1 rs11466445, TGFBR1 rs7034462, TGFBR1 rs11568785). Interestingly, we noted a significant interaction between "Appalachian self-identity" variables and NQO1 rs1800566. Multivariable logistic regression of cancer status in an over-dominant TGFB1 rs1800469/TGFBR1 rs11568785 model demonstrated a 3.03-fold reduction in cervical cancer odds. Similar decreased odds (2.78-fold) were observed in an over-dominant TGFB1 rs1800469/TGFBR1 rs7034462 model in subjects who had no sexual intercourse before age 18. CONCLUSIONS:This study reports novel associations between common low-penetrance alleles in the TGFB signaling cascade and modified risk of cervical cancer in Appalachian women. Furthermore, our unexpected findings associating Appalachian identity and NQO1 rs1800566 suggests that the complex environmental exposures that contribute to Appalachian self-identity in Appalachian cervical cancer patients represent an emerging avenue of scientific exploration.

Project description:Specific deletion of Tgfbr2 in FSP1+ fibroblasts (Tgfbr2fspKO) induced development of SCC in forestomach with 100% penetrance. Tgfbr2fspKO mice die by 7 weeks with a median survival of 38 days (Log rank p<0.001). Examination of Tgfbr2fspKO forestomach between embryonic day 16 (E16) and 5 weeks of age suggested that hyperplasia began during week 3 and was followed by dysplasia, carcinoma in situ, and invasive squamous cell carcinoma (SCC). The aim of this study was to elucidate genetic aberrations in the tumor associated stroma and SCC tumor using array comparative genomic hybridization (CGH) analysis. Laser capture micro-dissection was performed using formalin-fixed, paraffin-embedded, 5 week old Tgfbr2fspKO forestomach tissues. Genetic loss of cyclin-dependent kinase inhibitor, Cdkn2a/ p16Ink4A was found in laser captured epithelia of all three Tgfbr2fspKO forestomachs. Surprisingly, no genetic change was seen in the tumor associated stroma. Examination of human esophageal SCC showed a down-regulation of TGFβ receptor 2 (TβRII) in the stromal fibroblasts as well as increased inflammation and DNA damage. Published literature showed that loss of Cdkn2a/p16Ink4A tumor suppressor is the common event in human ESCCs. Our study suggests anti-inflammation may be a new therapeutic option in treating human SCCs with down-regulation of TβRII in the stroma. Laser capture microdissection of Tgfbr2flox/flox (n=3) and Tgfbr2fspKO (n=3) forestomach tissues was performed using an Arcturus XT (Life Technologies, CA, USA). Mouse background strain is C57Bl6. Frozen tissue sections on PEN membrane frame slides (Applied Biosystems) were H&E stained followed by dehydration using the standard protocol to improve visualization of the cells at the microscope. The epithelia and stroma were identified by morphology, captured using a low-power infrared laser pulse, and transferred onto a cap (Capsure™ Macro LCM Caps, Life Technologies). The DNA was extracted using a QIAamp DNA micro kit (Qiagen, CA, USA). Array-CGH was performed using test DNA from laser captured epithelia and stroma from Tgfbr2fspKO mice. Reference DNA was laser captured from the epithelia of normal forestomach of Tgfbr2flox/flox mice. DNA was labeled with Cy3 (test) or Cy5 (control) fluorescent dyes (Perkin Elmer, MA, USA) according to the BioPrime array CGH genomic labeling protocol (Invitrogen, Carlsbad, CA) and cleaned using Microcon YM-30 filters (Millipore, Billerica, MA). Hybridization was carried out using Mouse Genome CGH Microarray 4x180 K format from Agilent Technologies (Santa Clara, CA) according to CGH Procedures for Genomic DNA Analysis (Agilent Technologies). Slides were hybridized for 20 hours, washed, and scanned with an Agilent microarray scanner. Data was analyzed using Feature Extraction® and CGH Analytics® software packages (Agilent Technologies).

Dataset Information

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-? Superfamily.

Publications

A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-β Superfamily.

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