Deletion at Fragile Sites Is a Common and Early Event in Barrett's Esophagus

Lai, Lisa A.; Kostadinov, Rumen; Barrett, Michael T.; Peiffer, Daniel A.; Pokholok, Dimitry; Odze, Robert D.; Sanchez, Carissa A.; Maley, Carlo C.; Reid, Brian J.; Gunderson, Kevin L.; Rabinovitch, Peter S.

doi:10.1158/1541-7786.mcr-09-0529

Cited by 42 publications

(37 citation statements)

References 47 publications

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“…The quality and concentration of the extracted DNA were determined using a NanoDrop 2000 (Thermo Fisher Scientific, Wilmington, DE, USA). LOH at the c.A541G and c.A547G sites in the 10 cases enriched with TEKT4 variations was quantitatively assayed by using pyrosequencing technology basically as described previously 45,46 . Primer sequences were as follows: forward, GGAAGCCGAGCTCATCCG; biotinylated reverse, CCGGATCTGGCTCACT GCTT; sequencing, GGAGCTGCTGAAGAGA.…”

Section: Methodsmentioning

confidence: 99%

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

Jiang

Peng

et al. 2014

Nat Commun

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Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in B10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.

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Section: Methodsmentioning

confidence: 99%

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

Jiang

Peng

et al. 2014

Nat Commun

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“…92,93 Microsatellite instability with defect in mismatch repair genes 94 and nucleotide excision repair pathways, 95 genetic instability with allelic loss and ploidy abnormalities leading to loss of heterozygosity (LOH) viz. p53 LOH, p16LOH, 96 copy number alterations and deletions at fragile sites of the genome, 97,98 spindle checkpoint function failure like APC gene inactivation by promoter methylation, 99 pro-inflammatory cytokines and nitric oxide induced suppression of p53 activity, 100,101 increased human telomerase reverse transcriptase and human telomerase-associated RNA expression, 102 have all been demonstrated in patients progressing from BE to dysplasia and EAC. Alterations in p53 and p16 are early events in the metaplasia-dysplasia-adenocarcinoma sequence, followed by loss of cell cycle checkpoints.…”

Section: Reflux Disease Barrett's Esophagus (Be) and Esophageal Adenmentioning

confidence: 99%

Targeting chemokine pathways in esophageal adenocarcinoma

et al. 2014

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y These authors Contributed equally to this work. E sophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US and needs newer therapeutic and diagnostic strategies. Chronic inflammation plays a role in the pathogenesis of EAC and contributes to the dysplastic conversion of normal esophageal epithelium to Barrett's esophagus and frank adenocarcinoma. Chemokines play important roles in mediating inflammation and recent evidence implicates these ligands and their receptors in the development and spread of various tumors. We demonstrated that the chemokines IL8, CXCL1 and CXCL3 are significantly overexpressed during esophageal carcinogenesis and accompanied by amplification and demethylation of the chr4q21 gene locus. We also demonstrated that IL8 levels can be detected in serum of patients with EAC and can serve as potential biomarkers. We now demonstrate that inhibition of IL8 receptor, CXCR2, leads to decreased invasiveness of esophageal adenocarcinoma derived cells without affecting cellular proliferation. Taken together, these studies reveal the important roles that chemokines play in development of esophageal cancer and demonstrate that these pathways can serve as potential therapeutic targets.

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“…Pyrosequencing, a more sensitive method, was applied to quantitatively re-evaluate the cases with loss of TP53 or PIK3CA mutation after NCT as described previously (19,20). Allele frequencies were outputted as relative percentages using the Biotage PSQ software.…”

Section: Mutation Analysismentioning

confidence: 99%

Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

Jiang

Bao

et al. 2014

Cancer Research

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We investigated the loss of somatic mutations in TP53 and PIK3CA in breast cancer tissue after neoadjuvant chemotherapy (NCT) and the clinical relevance of the observed mutation profiles. Samples were derived from three cohorts: Cohort 1 consisting of 206 patients undergoing NCT with matched pre-and postchemotherapy tumor tissues; Cohort 2 consisting of 158 additional patients undergoing NCT; and Cohort 3, consisting of 81 patients undergoing chemotherapy with prechemotherapy tumor tissues. In the first cohort, somatic mutations in TP53 or PIK3CA were identified in 24.8% of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P < 0.001). Patients with initial TP53 and PIK3CA mutations who became negative for the mutations after NCT had a higher Miller-Payne score (P ¼ 0.008), improved disease-free survival, and improved overall survival than those with no change or the opposite change. The association of loss of mutations in TP53 and PIK3CA and improved survival was successfully validated in the second cohort. In addition, 28.4% of the tumors showed intratumoral heterogeneity of somatic mutations in TP53 or PIK3CA, whereas 71.6% were homogeneous, either with or without the mutations. Our data reveal the novel concept that chemotherapy may reduce mutation frequency in patients with breast cancer. Furthermore, the loss of somatic mutations in TP53 and PIK3CA may be translated to biomarkers for prognosis via further verification, which may optimize the choice of sequential therapy and improve patient survival. Cancer Res; 74(13); 3399-407. Ó2014 AACR.

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Deletion at Fragile Sites Is a Common and Early Event in Barrett's Esophagus

Cited by 42 publications

References 47 publications

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

Enriched variations in TEKT4 and breast cancer resistance to paclitaxel

Targeting chemokine pathways in esophageal adenocarcinoma

Favorable Prognostic Impact in Loss of TP53 and PIK3CA Mutations after Neoadjuvant Chemotherapy in Breast Cancer

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