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Genome-wide association study identifies four SNPs associated with response to platinum-based neoadjuvant chemotherapy for cervical cancer.

ABSTRACT: To identify genomic markers associated with the response to neoadjuvant chemotherapy (NACT) in patients with cervical cancer, we performed a three-stage genome-wide association study (GWAS) in the Han Chinese population. A total of 596 patients with stage IA2-IIIB cervical cancer were enrolled in this study. One single nucleotide polymorphism (SNP) (rs6812281, per allele OR = 2.37, P = 9.0 × 10^-9) located at 4q34.3 reached GWAS significance (P < 5.0 × 10^-8). Another three SNPs, rs4590782 (10q26.2, P = 1.59 × 10^-5, per allele OR = 0.48), rs1742101 (14q32.11, P = 7.11 × 10^-6, per allele OR = 0.52), and rs1364121 (16q23.3, P = 3.15 × 10^-6, per allele OR = 1.98), exhibited strong evidence of associations with response to neoadjuvant chemotherapy. Patients with a C allele (CT + CC) of rs4590782 had better 5-year overall survival rates (82.9% vs. 75.8%, P = 0.083) and 5-year disease-free survival rate (80.8% vs. 72.7%, P = 0.021) than those without a C allele. Our findings help to characterize the genetic etiology of the response to neoadjuvant chemotherapy in patients with cervical cancer.

SUBMITTER: Li X

PROVIDER: S-EPMC5264598 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies four SNPs associated with response to platinum-based neoadjuvant chemotherapy for cervical cancer.

Li Xiong X Huang Kecheng K Zhang Qinghua Q Zhou Jin J Sun Haiying H Tang Fangxu F Zhou Hang H Hu Ting T Wang Shaoshuai S Jia Yao Y Yang Ru R Chen Yile Y Cheng Xiaodong X Lv Weiguo W Wu Li L Xing Hui H Wang Lin L Zhou Shasha S Yao Yuan Y Wang Xiaoli X Suolang Quzhen Q Shen Jian J Xi Ling L Hu Junbo J Wang Hui H Chen Gang G Gao Qinglei Q Xie Xing X Wang Shixuan S Li Shuang S Ma Ding D

Scientific reports 20170125

To identify genomic markers associated with the response to neoadjuvant chemotherapy (NACT) in patients with cervical cancer, we performed a three-stage genome-wide association study (GWAS) in the Han Chinese population. A total of 596 patients with stage IA2-IIIB cervical cancer were enrolled in this study. One single nucleotide polymorphism (SNP) (rs6812281, per allele OR = 2.37, P = 9.0 × 10<sup>-9</sup>) located at 4q34.3 reached GWAS significance (P < 5.0 × 10<sup>-8</sup>). Another three S ...[more]

PMID: 28120872

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Project description:BackgroundThe 5-year cancer specific survival (CSS) for patients with muscle invasive urothelial carcinoma of the bladder (MIBC) treated with cystectomy alone is approximately 50%. Platinum based neoadjuvant chemotherapy (NAC) plus cystectomy results in a marginal 5-10% increase in 5-year CSS in MIBC. Interestingly, responders to NAC (<ypT2) have a 5-year CSS of 90% which is in stark contrast to the 30-40% CSS for those whose MIBC is resistance to NAC. While the implementation of NAC for MIBC is increasing, it is still not widely utilized due to concerns related to delay of cystectomy, potential side-effects, and inability to predict effectiveness. Recently suggested molecular signatures of chemoresponsiveness, which could prove useful in this setting, would be of considerable utility but are yet to be translated into clinical practice.MethodsmRNA expression data from a prior report on a NAC-treated MIBC cohort were re-analyzed in conjunction with the antibody database of the Human Protein Atlas (HPA) to identify candidate protein based biomarkers detectable by immunohistochemistry (IHC). These candidate biomarkers were subsequently tested in tissue microarrays derived from an independent cohort of NAC naive MIBC biopsy specimens from whom the patients were treated with neoadjuvant gemcitabine cisplatin NAC and subsequent cystectomy. The clinical parameters that have been previously associated with NAC response were also examined in our cohort.ResultsOur analyses of the available mRNA gene expression data in a discovery cohort (n = 33) and the HPA resulted in 8 candidate protein biomarkers. The combination of GDPD3 and SPRED1 resulted in a multivariate classification tree that was significantly associated with NAC response status (Goodman-Kruskal γ = 0.85 p<0.0001) in our independent NAC treated MIBC cohort. This model was independent of the clinical factors of age and clinical tumor stage, which have been previously associated with NAC response by our group. The combination of both these protein biomarkers detected by IHC in biopsy specimens along with the relevant clinical parameters resulted in a prediction model able to significantly stratify the likelihood of NAC resistance in our cohort (n = 37) into two well separated halves: low-26% n = 19 and high-89% n = 18, Fisher's exact p = 0.0002).ConclusionWe illustrate the feasibility of translating a gene expression signature of NAC response from a discovery cohort into immunohistochemical markers readily applicable to MIBC biopsy specimens in our independent cohort. The results from this study are being characterized in additional validation cohorts. Additionally, we anticipate that emerging somatic mutations in MIBC will also be important for NAC response prediction. The relationship of the findings in this study to the current understanding of variant histologic subtypes of MIBC along with the evolving molecular subtypes of MIBC as it relates to NAC response remains to be fully characterized.

Dataset Information

Genome-wide association study identifies four SNPs associated with response to platinum-based neoadjuvant chemotherapy for cervical cancer.

Publications

Genome-wide association study identifies four SNPs associated with response to platinum-based neoadjuvant chemotherapy for cervical cancer.

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