Cyclooxygenase-2 Expression in FAP Patients Carrying Germ Line <i>MYH</i> Mutations

Frattini, Milo; Carnevali, Ileana; Signoroni, Stefano; Balestra, Debora; Moiraghi, Maria Luisa; Radice, Paolo; Varesco, Liliana; Gismondi, Viviana; Ballardini, G.; Sala, Paola; Pilotti, Silvana; Bertario, Lucio

doi:10.1158/1055-9965.epi-05-0028

Cited by 9 publications

(4 citation statements)

References 19 publications

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“…Two colorectal cancer samples previously characterized were used as positive control for h-catenin and COX-2 (10,11). A gastrointestinal stromal tumor, molecularly characterized for KIT and PDGFRA, was used as positive control for KIT and PDGFRA staining, and a chordoma was used as positive control for PDGFRB reactivity as previously described (12).…”

Section: Methodsmentioning

confidence: 99%

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Cyclooxygenase-2 and Platelet-Derived Growth Factor Receptors as Potential Targets in Treating Aggressive Fibromatosis

Signoroni¹,

Frattini²,

Negri³

et al. 2007

Clinical Cancer Research

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Purpose: To explore the molecular bases of potential new pharmacologic targets in aggressive fibromatosis (desmoid tumor). Experimental Design: Tumor specimens from 14 patients surgically treated for aggressive fibromatosis (6 familial adenomatous polyposis and 8 sporadic cases), analyzed for adenomatous polyposis coli (APC) and CTNNB1 (b-catenin) mutations, were further investigated for h-catenin, cyclooxygenase-2 (COX-2), platelet-derived growth factor (PDGF) receptor a (PDGFRA)/PDGF receptor h (PDGFRB), their cognate ligands (PDGFA and PDGFB), and KIT using a comprehensive immunohistochemical, biochemical, molecular, and cytogenetic approach. Results: No CTNNB1 (b-catenin) mutations were found in the familial adenomatous polyposis patients, but previously reported activating mutations were found in six of the eight sporadic patients. All of the cases carrying an altered WNT pathway showed nuclear and cytoplasmic immunoreactivity for h-catenin, whereas h-catenin expression was restricted to the cytoplasm in the sporadic patients lacking CTNNB1 mutations. COX-2 protein and mRNA overexpression was detected in all 14 cases, together with the expression and phosphorylation of PDGFRA and PDGFRB, which in turn paralleled the presence of their cognate ligands. No PDGFRB mutations were found. The results are consistent with PDGFRA and PDGFRB activation sustained by an autocrine/paracrine loop. Conclusions: Aggressive fibromatosis is characterized by WNT/oncogene pathway alterations triggering COX-2^mediated constitutive coactivation of PDGFRA and PDGFRB, and may therefore benefit from combined nonsteroidal anti-inflammatory drug + tyrosine kinase inhibitor treatment.

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Section: Methodsmentioning

confidence: 99%

“…The analysis of mRNA expression of COX-2 was done on the basis of the protocol already reported (11). Amplified products were run on 2% agarose gel, stained with ethidium bromide, and visualized under UV light.…”

Section: Methodsmentioning

confidence: 99%

Cyclooxygenase-2 and Platelet-Derived Growth Factor Receptors as Potential Targets in Treating Aggressive Fibromatosis

Signoroni¹,

Frattini²,

Negri³

et al. 2007

Clinical Cancer Research

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“…Cerrahi tedavilerin hiçbiri ideal değildir ve birçok komplikasyona neden olabilir. Bu nedenle bir grup ilaç denenmiş ve nonsteroid antiinflamatuar ilaçların bu hastalardaki kolorektal karsinomların regresyonuna neden olduğu bildirilmiştir (18,19,20,21). Selekoksib 400 mg/gün, polip boyutlarını azaltmak için kullanılmakta olup FDA tarafından da onaylanmıştır.…”

Section: Discussionunclassified

Gardner Syndrome: Case Report

Demirci¹,

Sakin²,

Polat³

et al. 2015

Gulhane Med J

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Hakan DEMİRCİ (*), Yusuf Serdar SAKİN (*), Zülfikar POLAT (*), Murat KANTARCIOğLU (*), Ahmet UYGUN (*), Sait BAğCI (*), ÖZET Gardner Sendromu, gastrointestinal sistemde polipozis, osteoma, cilt ve yumuşak doku tümörleriyle karakterize otozomal dominant kalıtım gösteren, nadir görülen multisistemik bir hastalıktır. Bu sendromda, profilaktik rezeksiyon yapılmazsa hastalarda %100'e yakın oranda malignite gelişmektedir. Hastaların yaklaşık yarısında görülen osteomlar çoğunlukla baş bölgesinde yer almaktadırlar. Üç veya daha fazla sayıda osteom varlığında Gardner Sendromunun araştırılması gereklidir. Cilt bulguları; Epidermoid kist, fibrom, lipom, leiyomyom ve desmoid tümörleri içermektedir. Burada karın ağrısı ve ishal şikayetiyle kliniğimize başvuran polipozis koli ve osteomu olan 21 yaşındaki olguyu sunuyoruz.

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“…9 High COX-2 expression is also observed in another familial CRC syndrome, MUTYH-associated polyposis. 10 As COX-2 overexpression can be oncogenic, genetic variants that alter the expression of COX-2 may influence development of CRC. A large number of single nucleotide polymorphisms (SNPs) in and around the PTGS2 locus have been reported.…”

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confidence: 99%

An association between the PTGS2 rs5275 polymorphism and colorectal cancer risk in families with inherited non-syndromic predisposition

et al. 2013

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Recently our group completed a genome-wide linkage study investigating Australian and Spanish families with inherited risk of colorectal cancer (CRC). A minor linkage peak from that study located on chromosome 1 correlates with the location of a known CRC risk-modifying gene, prostaglandin synthase (PTGS2). PTGS2 encodes the inducible prostaglandin synthase enzyme cyclooxygenase-2 (COX-2). Prostaglandins are implicated in the initiation of carcinogenesis and progression of tumours. Sequencing of PTGS2 in a small subset of affected individuals identified a high frequency of the minor C allele of single nucleotide polymorphism rs5275. We then genotyped the rs5275 polymorphism in 183 affected and 223 unaffected individuals from our CRC predisposed families. Tests for association in the presence of linkage were made using family-based association tests. The C allele was found to be significantly associated (Po0.01) with diagnosis of hereditary non-syndromic CRC (P ¼ 0.0094, dominant model) and an earlier age of diagnosis (P ¼ 0.0089, heterozygous-advantage model). Interestingly, by stratifying the age of diagnosis data, we observed a speculative gender-discordant effect. Relative to other groups, female CC carriers were diagnosed less when young, but by 60 years of age were the most at risk group. Conversely, CT carriers of both genders showed a consistently earlier diagnosis relative to TT carriers. Our results suggest potential differential age-and genderdependent efficacies of chemopreventative COX-2 inhibitors in the context of non-syndromic colorectal cancer.

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Cyclooxygenase-2 Expression in FAP Patients Carrying Germ Line MYH Mutations

Cited by 9 publications

References 19 publications

Cyclooxygenase-2 and Platelet-Derived Growth Factor Receptors as Potential Targets in Treating Aggressive Fibromatosis

Cyclooxygenase-2 and Platelet-Derived Growth Factor Receptors as Potential Targets in Treating Aggressive Fibromatosis

Gardner Syndrome: Case Report

An association between the PTGS2 rs5275 polymorphism and colorectal cancer risk in families with inherited non-syndromic predisposition

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