**2. The association of SNPs with acute radiation dermatitis prediction**

Studies have investigated the association between SNPs and the severity of ARD that developed at the end of RT, primarily in patients receiving RT for head and neck and breast cancer.

#### **2.1 Breast CANCER patients**

A systematic review [48] of 16 cohort studies at low risk of bias, with a total of 4742 breast cancer patients treated with radiotherapy, summarized the data on whether SNPs predict ARD. Before the start of radiotherapy, all studies collected blood samples to identify SNPs and considered any manifestation of moist desquamation as a severe degree of ARD. Several studies included in this review presented statistically significant associations between SNPs and ARD. Twenty-nine SNPs were significantly associated with increased susceptibility to developing severe ARD and fifteen SNPs were significantly associated with decreased susceptibility to severe ARD (p < 0,05) However, it was not possible to compare the results in different samples because these associations were found in only one individual study. Furthermore, a wide variety of SNPs are being evaluated in individual studies, which makes it difficult to synthesize the data in a meta-analysis.

Considering the individual studies included in this systematic review, two SNPs had a significant association in more than one study, but with controversial results.

The rs8193 SNP in *CD44*, with CT and CT + TT genotypes, was associated with a 2.68-fold and 2.31-fold increase, respectively, in the risk of developing severe ARD in one study [49]. However, another study [50] found that the recessive model (TT) individually decreased the risk of developing severe ARD by 52%. *CD44* is a gene that involves transmembrane cell adhesion that is highly expressed on the surface of the dermis; however, its mechanism of action in healing remains unclear [51–56]. The meta-analysis found that the CC genotype is associated with the development of mild ARD, which did not manifest moist desquamation, and the CT genotype is associated with the development of severe ARD. However, with considerably low evidence certainty, further studies are required to investigate this SNP.

The rs3744355 SNP in *LIG3* was associated with the occurrence of ARD in one study (*p* = 0.0046) [57], but the authors did not report further information. Another study [50] found that the dominant pattern of this SNP was associated with a 68% decrease in the risk of developing severe ARD. *LIG3* acts on the DNA repair pathway by base excision, resulting from exposure to reactive oxygen species produced by exposure to RT [12, 57, 58].

Despite being evaluated in eight studies that composed this systematic review, the SNP *XRCC1* (rs25487) demonstrated a prevalence of 31% in breast cancer patients;

however, the data were not sufficient to allow the assessment of the association of this SNP with the severity of ARD.

The most prevalent SNPs were rs1800469 in *TGFβ1* (41%) and rs3957356 in *GSTA1* (36%). *TGFβ1* encodes a protein that acts on the inflammatory response pathways by repairing DNA lesions; however, it is not yet known whether SNPs can affect the function of this protein [59, 60]. *GSTA1* is involved in the production of reactive oxygen species, and SNPs can promote increased radiosensitivity through indirect damage to the DNA of skin cells [61]. Meta-analysis of genome association studies found that the CT genotype of the SNP rs3957356 in *GSTA1* increases the risk of severe ARD by approximately 6-fold, with low certainty of evidence.

Other SNPS associated with the development of mild and severe ARD in this systematic review are reported in **Table 1**.

Considering that these SNPs have presented low or considerably low certainty of evidence of association with ARD, further studies should be carried out to evaluate these SNPs to verify the existence of this association.
