• Association of transforming growth factor beta-1 single nucleotide polymorphisms with radiation-induced damage to normal tissues in breast cancer patients.

      Quarmby, Steven L; Fakhoury, H; Levine, Edward; Barber, J; Wylie, James P; Hajeer, A H; West, Catharine M L; Stewart, Alan L; Magee, Brian; Kumar, Shant; et al. (2003-02)
      PURPOSE: To investigate whether transforming growth factor beta-1 (TGFbeta1) single nucleotide polymorphisms were associated with the susceptibility of breast cancer patients to severe radiation-induced normal tissue damage. MATERIALS AND METHODS: PCR-RFLP assays were performed for TGFbeta1 gene polymorphisms on DNA obtained from 103 breast cancer patients who received radiotherapy. The G-800A, C-509T, T+869C and G+915C polymorphic sites were examined, and genotype and allele frequencies of two subgroups of patients were calculated and compared. RESULTS: The less prevalent -509T and +869C alleles were significantly associated with a subgroup of patients who developed severe radiation-induced normal tissue fibrosis (n=15) when compared with those who did not (n=88) (odds ratio=3.4, p=0.0036, and 2.37, p=0.035, respectively). Furthermore, patients with the -509TT or +869CC genotypes were between seven and 15 times more likely to develop severe fibrosis. CONCLUSIONS: These findings imply a role for the -509T and +869C alleles in the pathobiological mechanisms underlying susceptibility to radiation-induced fibrosis. Their predictive value would be limited to patients who are -509TT or +869CC, but if "fibrosis-associated" polymorphic sites in other genes could be identified, it may be possible to detect fibrosis prone individuals before radiotherapy with greater certainty.
    • Differential expression of cytokine genes in fibroblasts derived from skin biopsies of patients who developed minimal or severe normal tissue damage after radiotherapy.

      Quarmby, Steven L; West, Catharine M L; Magee, Brian; Stewart, Alan L; Hunter, Robin D; Kumar, Shant; Christie Hospital, Manchester, United Kingdom. steven.l.quarmby@man.ac.uk (2002-03)
      Curative radiotherapy for cancer patients requires the use of radiation doses that are limited by the tolerance of the surrounding normal tissues. Unfortunately, these tolerance doses vary not only between tissues but also between individuals. In a small proportion of sensitive patients, exposure to radiation can lead to severe irreversible morbidity and even death several months to years after treatment. At present these radiosensitive patients can be identified only retrospectively. Here we describe a cytokine microarray technique that was used to identify differentially expressed gene transcripts in fibroblasts obtained from a small group of patients who suffered either negligible or severe normal damage to tissues after radiotherapy. If our preliminary findings can be confirmed, the availability of such markers may eventually allow the prediction of outcome prior to commencement of radiotherapy, and thus allow modification of radiotherapy protocols to minimize adverse late effects, without compromising tumor control.