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iCancer Epidemiol Biomarkers Prev, Vol. 17, No. 10. (1 October 2008), pp. 2565-2571./ibr /br
/Methionine-dependence phenotype (MDP) refers to the reduced ability of cells to proliferate when
methionine is restricted and/or replaced by its immediate precursor homocysteine. MDP is a
characteristic of human tumors in vivo, human tumor cell lines, and normal somatic tissue in some
individuals. It was hypothesized that MDP is a risk factor for developing breast cancer in BRCA
(BRCA1 and BRCA2) germline mutation carriers. To test the hypothesis, human peripheral blood
lymphocytes of BRCA carriers with and without breast cancer and healthy non-carrier relatives
(controls) were cultured for 9 days in medium containing either 0.1 mmol/L L-methionine or 0.2
mmol/L D,L-homocysteine, with the ratio of viable cell growth in both types of medium after 9 days
used to calculate the methionine-dependence index (MDI), a measure of MDP. We also tested whether
MDP was associated with common polymorphisms in methionine metabolism. Viable cell growth, MDI, and
polymorphism frequency in MTRR (A66G and C524T) and MTHFR (A1298C and A1793G) did not differ among
the study groups; however, MDI tended to be higher in BRCA carriers with breast cancer than those
without and was significantly increased in MTHFR 677T allele carriers relative to wild-type
carriers (P = 0.017). The presence of MTR A2756G mutant allele and MTHFR C677T mutant allele in
carriers was associated with increased breast cancer risk [odds ration, 3.2 (P = 0.16; 95%
confidence interval, 0.76-13.9) and 3.9 (P = 0.09; 95% confidence interval, 0.93-16.3),
respectively]. The results of this study support the hypothesis that defects in methionine
metabolism may be associated with breast cancer risk in BRCA carriers. (Cancer Epidemiol Biomarkers
Prev 2008;17(10):2565-71) 10.1158/1055-9965.EPI-08-0140br /iSasja Beetstra, Graeme Suthers,
Varinderpal Dhillon, Carolyn Salisbury, Julie Turner, Meryl Altree, Ross Mckinnon, Michael Fenech/i
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