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Gene signatures of drug resistance predict patient survival in colorectal cancer.

Zheng Y, Zhou J, Tong Y - Pharmacogenomics J. (2014)

Bottom Line: Biomarkers are proven to be successful in characterizing patients into different response groups.These score systems exhibited robustness in stratify patients in two independent clinical studies.Patients with high scores in all three drugs exhibited the lowest survival.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA [2] Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.

ABSTRACT
Different combinations of 5-fluorouracil (5-FU), oxaliplatin, irinotecan and other newly developed agents have been used to treat colorectal cancer. Despite the advent of new treatment regimens, the 5-year survival rate for metastatic colorectal cancer remains low (~10%). Knowing the drug sensitivity of a given tumor for a particular agent could significantly impact decision making and treatment planning. Biomarkers are proven to be successful in characterizing patients into different response groups. Using survival prediction analysis, we have identified three independent gene signatures, which are associated with sensitivity of colorectal cancer cells to 5-FU, oxaliplatin or irinotecan. On the basis of the three gene signatures, three score systems were developed to stratify patients from sensitive to resistance. These score systems exhibited robustness in stratify patients in two independent clinical studies. Patients with high scores in all three drugs exhibited the lowest survival.

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Related in: MedlinePlus

Kaplan–Meier curves were drawn for conditions as follows. (a) Patients in the validation data set were similarly dichotomized into high (H_FU) and low (L_FU) drug-resistant groups based on the resistance score of 5-fluorouracil (5-FU) (b) Patients in the validation data set were similarly dichotomized into high (H_Oxa) and low (L_Oxa) drug-resistant groups based on the resistance score of oxaliplatin. (c) Patients in the validation data set were similarly dichotomized into high (H_SN) and low (L_SN) drug-resistant groups based on resistance score of SN38.
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fig4: Kaplan–Meier curves were drawn for conditions as follows. (a) Patients in the validation data set were similarly dichotomized into high (H_FU) and low (L_FU) drug-resistant groups based on the resistance score of 5-fluorouracil (5-FU) (b) Patients in the validation data set were similarly dichotomized into high (H_Oxa) and low (L_Oxa) drug-resistant groups based on the resistance score of oxaliplatin. (c) Patients in the validation data set were similarly dichotomized into high (H_SN) and low (L_SN) drug-resistant groups based on resistance score of SN38.

Mentions: Gene Ontology analysis (Figure 1c1) indicated that these 496 genes were enriched in functions involving cell proliferation (39.7%), response to stimulus (16.1%), growth (15.9%), rhythmic process (11%), viral reproduction (8.6%) and cellular process (8.4%). Ingenuity analysis indicated that the top five enriched signaling networks (Figure 1c2) were: cell death, cellular compromise, antimicrobial response; cellular function and maintenance, molecular transport, cell signaling; gene expression, DNA replication, recombination, and repair, cell-to-cell signaling and interaction; cell cycle, reproductive system development and function, cell-to-cell signaling and interaction; and cellular growth and proliferation, skeletal and muscular system development and function, lipid metabolism. The core nodes in the signaling networks include NFKB complex, CACNA1A, SMARCA4, PI3K complex and MAPK (Supplementary Data 1, Figures 3, 4, 5).


Gene signatures of drug resistance predict patient survival in colorectal cancer.

Zheng Y, Zhou J, Tong Y - Pharmacogenomics J. (2014)

Kaplan–Meier curves were drawn for conditions as follows. (a) Patients in the validation data set were similarly dichotomized into high (H_FU) and low (L_FU) drug-resistant groups based on the resistance score of 5-fluorouracil (5-FU) (b) Patients in the validation data set were similarly dichotomized into high (H_Oxa) and low (L_Oxa) drug-resistant groups based on the resistance score of oxaliplatin. (c) Patients in the validation data set were similarly dichotomized into high (H_SN) and low (L_SN) drug-resistant groups based on resistance score of SN38.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4381104&req=5

fig4: Kaplan–Meier curves were drawn for conditions as follows. (a) Patients in the validation data set were similarly dichotomized into high (H_FU) and low (L_FU) drug-resistant groups based on the resistance score of 5-fluorouracil (5-FU) (b) Patients in the validation data set were similarly dichotomized into high (H_Oxa) and low (L_Oxa) drug-resistant groups based on the resistance score of oxaliplatin. (c) Patients in the validation data set were similarly dichotomized into high (H_SN) and low (L_SN) drug-resistant groups based on resistance score of SN38.
Mentions: Gene Ontology analysis (Figure 1c1) indicated that these 496 genes were enriched in functions involving cell proliferation (39.7%), response to stimulus (16.1%), growth (15.9%), rhythmic process (11%), viral reproduction (8.6%) and cellular process (8.4%). Ingenuity analysis indicated that the top five enriched signaling networks (Figure 1c2) were: cell death, cellular compromise, antimicrobial response; cellular function and maintenance, molecular transport, cell signaling; gene expression, DNA replication, recombination, and repair, cell-to-cell signaling and interaction; cell cycle, reproductive system development and function, cell-to-cell signaling and interaction; and cellular growth and proliferation, skeletal and muscular system development and function, lipid metabolism. The core nodes in the signaling networks include NFKB complex, CACNA1A, SMARCA4, PI3K complex and MAPK (Supplementary Data 1, Figures 3, 4, 5).

Bottom Line: Biomarkers are proven to be successful in characterizing patients into different response groups.These score systems exhibited robustness in stratify patients in two independent clinical studies.Patients with high scores in all three drugs exhibited the lowest survival.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA [2] Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.

ABSTRACT
Different combinations of 5-fluorouracil (5-FU), oxaliplatin, irinotecan and other newly developed agents have been used to treat colorectal cancer. Despite the advent of new treatment regimens, the 5-year survival rate for metastatic colorectal cancer remains low (~10%). Knowing the drug sensitivity of a given tumor for a particular agent could significantly impact decision making and treatment planning. Biomarkers are proven to be successful in characterizing patients into different response groups. Using survival prediction analysis, we have identified three independent gene signatures, which are associated with sensitivity of colorectal cancer cells to 5-FU, oxaliplatin or irinotecan. On the basis of the three gene signatures, three score systems were developed to stratify patients from sensitive to resistance. These score systems exhibited robustness in stratify patients in two independent clinical studies. Patients with high scores in all three drugs exhibited the lowest survival.

Show MeSH
Related in: MedlinePlus