TGF-?1 levels in pre-treatment plasma identify breast cancer patients at risk of developing post-radiotherapy fibrosis

The late radiotherapy normal tissue injury phenotypes of telangiectasia, fibrosis and atrophy in breast cancer patients have distinct genotype-dependent causes

“…The observed contributions to fibrosis risk of an early severe acute reaction, which can trigger an inflammatory response, and the TGFb1 (C-509T) SNP, which has been associated with increased serum levels of the pro-inflammatory TGFb1 cytokine following radiotherapy, are consistent with the established link between fibrosis and inflammation (Awad et al, 1988;Zugmaier et al, 1991;Anscher et al, 1997;Martin et al, 1997Martin et al, , 2000Grainger et al, 1999;Li et al, 1999). Additional genetic factors are presumably responsible for the radiosensitivity that causes the severe acute reaction and a number of variant genes have been implicated in abnormal cell radiosensitivity (Moullan et al, 2003;Chang-Claude et al, 2005;De Ruyck et al, 2005;Fernet and Hall, 2005), but none of the eight candidate gene SNP analysed in this study was significantly associated with an early acute reaction.…”

“…The genes and corresponding SNP were chosen because XRCC1 (R399Q) and APE-1 (D126E) have been implicated in DNA repair (Hu et al, 2001;Chang-Claude et al, 2005;De Ruyck et al, 2005), TGFb1 (C-509T) and CX3CR1 (G745A) have been implicated in inflammation and fibrosis (Zugmaier et al, 1991;Randall and Coggle, 1995;Anscher et al, 1997;Li et al, 1999;Martin et al, 2000;McDermott et al, 2001;Gauldie et al, 2003), MTHFR (C667T), MS (A2756G) and DHFR (19 bp del intron 1) involved in folate metabolism (Johnson et al, 2004;Linnebank et al, 2004), epoxide hydrolase (Hyl1 Y113H) implicated in oxidative stress (Lebailly et al, 2002), and XRCC1 (R399Q) have been associated with susceptibility to breast cancer (Moullan et al, 2003). Additionally, several gene polymorphism have previously been implicated in late radiation-induced tissue damage (Awad et al, 1988;El-Gamel et al, 1999;Grainger et al, 1999;Quarmby et al, 2003;Andreassen et al, 2005;De Ruyck et al, 2005Brem et al, 2006), and TGFb1 and Hyl1 are induced following exposure to ionising radiation (Anscher et al, 1997;Martin et al, 1997).…”

“…Radiation induces long-term TGFb1 overexpression probably owing in part to oxidative stress and an inflammatory response (Randall and Coggle, 1995;Anscher et al, 1997;Martin et al, 1997Martin et al, , 2000O'Sullivan and Levin, 2003), and a causal relationship between increased TGFb production and the development of tissue fibrosis has been reported in animal models (Zugmaier et al, 1991;Terrell et al, 1993;Sanderson et al, 1995;Clouthier et al, 1997). Most significantly, elevated serum TGFb1 levels were correlated with an increased risk of fibrosis in breast and lung cancer patients (Awad et al, 1988;Anscher et al, 1997;Grainger et al, 1999;Li et al, 1999) and a comparison of the genotypes of unaffected and affected patients has been genetically associated with functional polymorphisms in the TGFb1 gene (Awad et al, 1988;El-Gamel et al, 1999;Quarmby et al, 2003;Andreassen et al, 2005).…”

No association between SNPs regulating TGF-β1 secretion and late radiotherapy toxicity to the breast: Results from the RAPPER study

“…Some studies have reported a correlation between elevated serum TGF-β1 levels and increased fibrosis in breast cancer patients [18]. However, others have not found such associations [19].…”

Molecular markers for prediction of risk of radiation-related injury to normal tissue

“…20 Other studies tested the possibility that, in sensitive patients, constitutive alterations in the expression levels of specific RNAs could be associated with IR toxicity, and identified genes with different expression both in the normal injured tissue and in peripheral blood. 5,19,[21][22][23][24][25][26][27][28] By assessing these genes at baseline, i.e. before the start of therapy, it could be possible to use them as biomarkers for predicting or monitoring normal tissue toxicity of radiation therapy, 29 and thus select cases that can be directed towards a specific therapy, or change radiotherapy dosefractionation prescription or plan dose distributions.…”