DNA-Repair Gene Polymorphisms Predict Favorable Clinical Outcome Among Patients With Advanced Squamous Cell Carcinoma of the Head and Neck Treated With Cisplatin-Based Induction Chemotherapy

Quintela‐Fandino, Miguel; Hitt, Ricardo; Medina, Pedro; Gamarra, Soledad; Manso, Luis; Cortés, Javier; Sanchez-Cespedes, Montse

doi:10.1200/jco.2006.05.8768

Cited by 128 publications

(128 citation statements)

References 35 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…Melanoma patients with the wild-type genotype treated with cisplatin, however, had shorter survival rates and worse response [45]. Additionally, it has been shown that increased variant alleles in ERCC2 and XRCC1 confer a worse survival for non-small cell lung cancer patients treated with platinum drugs [8], whereas an increasing number of variant alleles in squamous head and neck cancer treated with cisplatin had increased survival rates [22]. Even though there are a few identified genetic predictors of platinum-based treatment outcome in DNA repair genes, there is a paucity of data on genetic variants important in platinum-induced toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Several candidate gene approaches have been implemented to identify the basis of response or toxicity to cisplatin, which have included the use of tumor cell types and model systems [18][19][20]. Variants in candidate genes such as glutathione S-transferases, ERCC1, ERCC2, and XRCC1 have been shown to alter response to cisplatin [21,22]. Candidate gene studies with these variant alleles, however, have also lead to inconsistent results [21].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

Objectives-Cisplatin is a widely used chemotherapeutic agent; however, nephrotoxicity and neuropathy are obstacles for drug efficacy. Little is known about the genes or genetic variants contributing to the risk of developing these toxicities or chemotherapeutic response. Thus, we have applied a cell-based model to identify and characterize previously unknown genes that may be involved in cellular susceptibility to cisplatin.Methods-Lymphoblastoid cell lines from 27 large Centre d'Etude du Polymorphisme Humain pedigrees were used to elucidate the genetic contribution to cisplatin-induced cytotoxicity. Phenotype was defined as cell growth inhibition following exposure of cell lines to increasing concentrations of cisplatin for 48 h.Results-Significant heritability, ranging from 0.32 to 0.43 (P < 10 −7 ), was found for the cytotoxic effects of each concentration (1, 2.5, 5, 10, and 20 μmol/l) and IC50, the concentration required for 50% cell growth inhibition. Linkage analysis revealed 11 genomic regions on six chromosomes with logarithm of odds (LOD) scores above 1.5 for cytotoxic phenotypes. The highest LOD score was found on chromosome 4q21.3−q35.2 (LOD = 2.65, P = 2.4 × 10 −4 ) for 5 μmol/l cisplatin. Quantitative transmission disequilibrium tests were performed using 191 973 nonredundant single nucleotide polymorphisms (SNPs) located in the 1 LOD confidence interval of these 11 regions. Twenty SNPs, with 10 SNPs located in five genes, were significantly associated with cisplatin-induced cytotoxicity (P ≤ 1 × 10 −4 ). Four of these 20 SNPs were found to explain over 10% of the variation in cisplatininduced apoptosis.Conclusions-Our results suggest that genetic factors involved in cytotoxicity also contribute to cisplatin-induced apoptosis. These cell lines provide a paradigm to identify previously unknown pharmacogenetic variants associated with drug cytotoxicity.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

View full text Add to dashboard Cite

show abstract

“…All these SNPs have been related to platinum and radiotherapy response and/or risk of cancer in other type of tumors. [9][10][11][12]24,30,31 Genotypes were determined by TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA, USA) for all SNPs, except rs1800975 (or which the KASPar SNP genotyping system was used (KBioscience, Hoddesdon, UK). Allelic discrimination was carried out using the ABI PRISM 7900 Sequence Detection System (Applied Biosystems).…”

Section: Dna Extraction and Genotypingmentioning

confidence: 99%

“…Alterations in NER genes expression 8 as well as the presence of single nucleotide polymorphisms (SNPs) 9 are correlated with cisplatin resistance. SNPs in the ERCC1 and ERCC2 10 genes have been found to be associated with platinum response in different clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

et al. 2009

View full text Add to dashboard Cite

Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio ¼ 4.9, 95% confidence interval ¼ 1.64-14.54, adjusted P-value ¼ 0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median ¼ 184 months, compared with 240 months for T T homozygotes; hazard ratio ¼ 5.76, 95% confidence interval ¼ 1.30-25.55; P-value ¼ 0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value ¼ 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients.

show abstract

“…Loss of NER capacity has been demonstrated in testicular cancer (10), where it may have important implications for susceptibility to cisplatinum-based chemotherapy (11). NER gene polymorphisms have been associated with response to cis-platinum in head and neck (12), lung (13), and breast cancer (14). Constitutively low NER levels have been reported in the peripheral blood lymphocytes (PBLs) of patients with breast cancer (15,16) and their relatives (17).…”

mentioning

confidence: 99%

Nucleotide excision repair deficiency is intrinsic in sporadic stage I breast cancer

Latimer

Johnson

Kelly

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only approximately 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or that they have not yet been identified. In striking contrast, we now show that 19 of 19 stage I breast tumors tested with the functional unscheduled DNA synthesis assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls (n = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis. By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples versus normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNase protection. These results were confirmed at the protein level for five NER gene products. Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early-stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis-platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium.human primary breast cell explant culture | human breast tumor explant culture | breast epithelial attached epispher | hypermutability

show abstract

DNA-Repair Gene Polymorphisms Predict Favorable Clinical Outcome Among Patients With Advanced Squamous Cell Carcinoma of the Head and Neck Treated With Cisplatin-Based Induction Chemotherapy

Abstract: Using a multivariate model, the presence of polymorphic variants in DNA-repair genes are powerful prognosis factors and response to cisplatin predictors among SCCHN patients.

Cited by 128 publications

References 35 publications

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

Nucleotide excision repair deficiency is intrinsic in sporadic stage I breast cancer

Contact Info

Product

Resources

About