Functional promoter rs2868371 variant of HSPB1 associates with radiation-induced esophageal toxicity in patients with non-small-cell lung cancer treated with radio(chemo)therapy
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, USA. Radiotherapy and Oncology
(Impact Factor: 4.36).
09/2011; 101(2):271-7. DOI: 10.1016/j.radonc.2011.08.039
We investigated the association between single-nucleotide polymorphisms (SNPs) in the heat shock protein beta-1 (HSPB1) gene and the risk of radiation-induced esophageal toxicity (RIET) in patients with non-small-cell lung cancer (NSCLC).
The experimental dataset comprised 120 NSCLC patients who were treated with radio(chemo)therapy between 2005 and 2009, when novel radiation techniques were implemented at MD Anderson. The validation dataset comprised 181 NSCLC patients treated between 1998 and 2004. We genotyped two SNPs of the HSPB1 gene (rs2868370 and rs2868371) by TaqMan assay.
Univariate and multivariate analyses of the experimental dataset showed that the CG/GG genotypes of HSPB1 rs2868371 were associated with significantly lower risk of grade ⩾3 RIET than the CC genotype (univariate hazard ratio [HR] 0.30; 95% confidence interval [CI], 0.10-0.91; P=0.033; multivariate HR 0.29; 95% CI, 0.09-0.97; P=0.045). This difference in risk was replicated in the validation cohort despite the different radiation techniques used during that period.
The CG/GG genotypes of HSPB1 rs2868371 were associated with lower risk of RIET, compared with the CC genotype in patients with NSCLC treated with radio(chemo)therapy. This finding should be validated in large multi-institutional prospective trials.
Available from: Laura Fachal
- "Our negative results are in agreement with recent reports on the Radiogenomics field [31,35–37]. While large and well powered studies fail to detect significant associations with genes identified until that time as good candidates, the number of positive results on large cohorts after multiple testing corrections  or validated on a independent cohort  are anecdotal. These evidences suggest that the effect conferred by the majority of genes traditionally associated with the radiosensitivity of normal tissue may be clinically irrelevant, or even nonexistent. "
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ABSTRACT: Background and purpose:
We have performed a case-control study among prostate cancer patients treated with three-dimensional conformational radiotherapy (3D-CRT) in order to investigate the association between single nucleotide polymorphisms (SNPs), treatment and patient features with gastrointestinal and genitourinary acute toxicity.
Material and methods:
A total of 698 patients were screened for 14 SNPs located in the ATM, ERCC2, LIG4, MLH1 and XRCC3 genes. Gastrointestinal and genitourinary toxicities were recorded prospectively using the Common Terminology Criteria for Adverse Events v3.0.
The XRCC3 SNP rs1799794 (G/G OR=5.65; 95% CI: 1.95-16.38; G/A OR=2.75; 95% CI: 1.25-6.05; uncorrected p-value=2.8×10(-03); corrected p-value=0.03; FDR q-value=0.06) as well as the mean dose received by the rectum (OR=1.06; 95% CI: 1.02-1.1; uncorrected p-value=2.49×10(-03); corrected p-value=0.03; FDR q-value=0.06) were significantly associated with gastrointestinal toxicity after correction for multiple testing. Those patients who undergone previous prostatectomy were less prone to develop genitourinary toxicity (OR=0.38; 95% CI: 0.18-0.71; uncorrected p-value=4.95×10(-03); corrected p-value=0.03; FDR q-value=0.08). Our study excludes the possibility of a >2-fold risk increase in genitourinary acute toxicity being due to rs1801516 ATM SNP, the rs1805386 and rs1805388 LIG4 markers, as well as all the SNPs evaluated in the ERCC2, MLH1 and XRCC3 genes.
The XRCC3 rs1799794 SNP and the mean dose received by the rectum are associated with the development of gastrointestinal toxicity after 3D-CRT.
Radiotherapy and Oncology 10/2012; 105(3). DOI:10.1016/j.radonc.2012.09.013 · 4.36 Impact Factor
Radiotherapy and Oncology 11/2011; 101(2):237-9. DOI:10.1016/j.radonc.2011.10.019 · 4.36 Impact Factor
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ABSTRACT: Individualised, isotoxic, accelerated radiotherapy (INDAR) allows the delivery of high biological radiation doses, but the long-term survival associated with this approach is unknown.
Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included.
Patients (1002) with stage III NSCLC were diagnosed, of which 938 had T4 and/or N2-N3 disease. Patients treated with curative intent were staged with FDG-PET scans and a contrast-enhanced CT or an MRI of the brain. There were no shifts over time in the patient or tumour characteristics at diagnosis. The number of stage III NSCLC patients remained stable over time, but the proportion treated with palliative intent decreased from 47% in 2002 to 37% in 2008, and the percentage treated with chemo-radiation (RT) increased from 24.6% in 2002 to 47.8% in 2008 (p<0.001). The proportion of surgical patients remained below 5%. Sequential chemotherapy and conventional RT resulted in a median and a 5-year survival of 17.5 months and 8.4%, respectively, whereas with sequential chemotherapy and INDAR this was 23.6 months and 31%, respectively (p<0.001). Concurrent chemotherapy and INDAR was associated with a median and 2-year survival that was not reached and 66.7%, respectively (p=0.004).
The proportion of patients treated with a curative intention with chemo-RT has increased markedly over time of observation. INDAR is associated with longer survival when compared to standard dose RT alone given with or without chemotherapy.
Radiotherapy and Oncology 11/2011; 102(2):228-33. DOI:10.1016/j.radonc.2011.10.010 · 4.36 Impact Factor
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