Cancer Res Treat.  2017 Apr;49(2):464-472. 10.4143/crt.2016.256.

DNA Methyltransferase Gene Polymorphisms for Prediction of Radiation-Induced Skin Fibrosis after Treatment of Breast Cancer: A Multifactorial Genetic Approach

• Terrazzino S
• Deantonio
• Cargnin S
• Donis L
• Pisani C
• Masini L
• Gambaro G
• Canonico P
• Genazzani
• Krengli M

• KMID: 2378119
• DOI: http://doi.org/10.4143/crt.2016.256

Abstract

PURPOSE
This study was conducted to investigate the role of four polymorphic variants of DNA methyltransferase genes as risk factors for radiation-induced fibrosis in breast cancer patients. We also assessed their ability to improve prediction accuracy when combined with mitochondrial haplogroup H, which we previously found to be independently associated with a lower hazard of radiation-induced fibrosis.
MATERIALS AND METHODS
DNMT1 rs2228611,DNMT3A rs1550117,DNMT3A rs7581217, and DNMT3B rs2424908 were genotyped by real-time polymerase chain reaction in 286 Italian breast cancer patients who received radiotherapy after breast conserving surgery. Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale. The discriminative accuracy of genetic models was assessed by the area under the receiver operating characteristic curves (AUC).
RESULTS
Kaplan-Meier curves showed significant differences among DNMT1 rs2228611 genotypes in the cumulative incidence of grade ≥ 2 subcutaneous fibrosis (log-rank test p-value= 0.018). Multivariate Cox regression analysis revealed DNMT1 rs2228611 as an independent protective factor for moderate to severe radiation-induced fibrosis (GG vs. AA; hazard ratio, 0.26; 95% confidence interval [CI], 0.10 to 0.71; p=0.009). Adding DNMT1 rs2228611 to haplogroup H increased the discrimination accuracy (AUC) of the model from 0.595 (95% CI, 0.536 to 0.653) to 0.655 (95% CI, 0.597 to 0.710).
CONCLUSION
DNMT1 rs2228611 may represent a determinant of radiation-induced fibrosis in breast cancer patients with promise for clinical usefulness in genetic-based predictive models.

Keyword

Breast neoplasms; Fibrosis; Radiosensitivity; Skin; Single nucleotide polymorphism

MeSH Terms

Breast Neoplasms*
Breast*
Discrimination (Psychology)
DNA*
Fibrosis*
Genotype
Humans
Incidence
Mastectomy, Segmental
Models, Genetic
Polymorphism, Single Nucleotide
Protective Factors
Radiation Tolerance
Radiotherapy
Real-Time Polymerase Chain Reaction
Risk Factors
ROC Curve
Skin*
DNA

Figure

• 

  Fig. 1. Kaplan-Meier plot of cumulative grade ≥ 2 radiation-induced fibrosis in breast cancer patients by DNMT1 rs2228611 genotypes (p=0.018, log-rank test).

• 

  Fig. 2. Receiver operating characteristic curve curves for prediction of grade ≥ 2 radiation-induced fibrosis based on different combinations of DNMT1 rs2228611 and/or mitochondrial haplogroup H, as described in Table 3. Model 5 vs. model 1, p=0.053; model 5 vs. model 3, p=0.009; model 5 vs. model 4, p=0.93. Model 2 is not shown since it is equivalent to model 3. AUC, area under the receiver operating characteristic curves; CI, confidence interval.

• 

  Fig. 3. Kaplan-Meier plot of cumulative grade ≥ 2 radiation-induced fibrosis in breast cancer patients by sum risk scores based on model 5, which combines mitochondrial haplogroup H with the recessive contrast of DNMT1 rs2228611 (p trend=0.0005, log-rank test).

Reference

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