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Allelic imbalance at p53 and microsatellite instability are predictive markers for resistance to chemotherapy in gastric carcinoma.

ABSTRACT: Combined treatment with 5-fluorouracil and cisplatin (FP chemotherapy) is an effective neoadjuvant regimen for gastric carcinoma. However, it is ineffective in half of all patients. This study tests the hypothesis that genetic markers might identify those patients with gastric cancer who would respond to neoadjuvant FP chemotherapy.A total of 23 patients with gastric carcinoma were treated with neoadjuvant chemotherapy. Pretreatment biopsy specimens before neoadjuvant chemotherapy were obtained from 15 of 23 patients, and resected tumors were obtained from all 23. Genetic studies were performed to detect allelic imbalance (AI), microsatellite instability (MSI), and K-ras mutation.A clinical response was observed in 13 of 23 patients. Kaplan-Meier survival curve showed that clinical responder group had a significantly higher likelihood of overall survival (P = 0.0165), compared with nonresponder group. In 23 resection specimens, 10 of 23 tumors presented AI at the p53 locus and/or MSI; 8 of the 10 tumors were nonresponders, while 12 of 13 tumors without p53 AI or MSI were responders (P = 0.0007). In 15 pretreatment biopsy specimens, 8 tumors had p53 AI and/or MSI; 7 of the 8 tumors were nonresponders, while 6 of 7 tumors without p53 AI or MSI were responders to preoperative chemotherapy (P = 0.008). Tumors with AI at the p53 locus and/or MSI were significantly more resistant to neoadjuvant chemotherapy. No relationship was found between K-ras mutations and responses.Analysis for p53 AI and MSI might represent a clinically useful approach to predicting the response to neoadjuvant FP chemotherapy in gastric carcinoma.

SUBMITTER: Yashiro M

PROVIDER: S-EPMC2865194 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Allelic imbalance at p53 and microsatellite instability are predictive markers for resistance to chemotherapy in gastric carcinoma.

Yashiro Masakazu M Inoue Toru T Nishioka Nobuaki N Matsuoka Tasuku T Boland C Richard CR Hirakawa Kosei K

Annals of surgical oncology 20090714 10

<h4>Background</h4>Combined treatment with 5-fluorouracil and cisplatin (FP chemotherapy) is an effective neoadjuvant regimen for gastric carcinoma. However, it is ineffective in half of all patients. This study tests the hypothesis that genetic markers might identify those patients with gastric cancer who would respond to neoadjuvant FP chemotherapy.<h4>Materials and methods</h4>A total of 23 patients with gastric carcinoma were treated with neoadjuvant chemotherapy. Pretreatment biopsy specime ...[more]

PMID: 19597886

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Project description:Simple Summary Osteosarcoma (OS) is a highly heterogenous cancer, making the identification of genetic driving factors difficult. Genetic factors, such as heritable mutations of Rb1 and TP53, are associated with an increased risk of OS. We previously generated pigs carrying a mutated TP53 gene, which develop OS at high frequency. RNA sequencing and allelic expression imbalance analysis identified an amplification of YAP1 involved in p53- dependent OS progression. The inactivation of YAP1 inhibits proliferation, migration, and invasion, and leads to the silencing of TP63 and reconstruction of p16 expression in p53-deficient porcine OS cells. This study confirms the importance of p53/YAP1 network in cancer. Abstract Osteosarcoma (OS) is a primary bone malignancy that mainly occurs during adolescent growth, suggesting that bone growth plays an important role in the aetiology of the disease. Genetic factors, such as heritable mutations of Rb1 and TP53, are associated with an increased risk of OS. Identifying driver mutations for OS has been challenging due to the complexity of bone growth-related pathways and the extensive intra-tumoral heterogeneity of this cancer. We previously generated pigs carrying a mutated TP53 gene, which develop OS at high frequency. RNA sequencing and allele expression imbalance (AEI) analysis of OS and matched healthy control samples revealed a highly significant AEI (p = 2.14 × 10−39) for SNPs in the BIRC3-YAP1 locus on pig chromosome 9. Analysis of copy number variation showed that YAP1 amplification is associated with the AEI and the progression of OS. Accordingly, the inactivation of YAP1 inhibits proliferation, migration, and invasion, and leads to the silencing of TP63 and reconstruction of p16 expression in p53-deficient porcine OS cells. Increased p16 mRNA expression correlated with lower methylation of its promoter. Altogether, our study provides molecular evidence for the role of YAP1 amplification in the progression of p53-dependent OS.

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Allelic imbalance at p53 and microsatellite instability are predictive markers for resistance to chemotherapy in gastric carcinoma.

Publications

Allelic imbalance at p53 and microsatellite instability are predictive markers for resistance to chemotherapy in gastric carcinoma.

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