title: Association of aberrations in one-carbon metabolism with molecular phenotype and grade of breast cancer.
abstract: We have earlier demonstrated the role of aberrant one-carbon metabolism in the etiology of breast cancer. In the current study, we examine the clinical utility of these factors in predicting the subtype of breast cancer and as indicators of disease progression. Polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and PCR-amplified fragment length polymorphism (AFLP) approaches were used for genetic analysis. Plasma folate and homocysteine were measured using Axsym folate kit and reverse phase HPLC, respectively. Multiple linear regression models were used to test the predictability of disease progression. Luminal A subtype was associated with late age of onset, higher body mass index and lack of family history of breast cancer. Thymidylate synthase (TYMS) 5'-UTR 28 bp tandem repeat (OR: 2.09, 95% CI: 1.05-4.16) and methylene tetrahydrofolate reductase (MTHFR) C677T (OR: 4.10, 95% CI: 1.40-11.95) were strongly associated with Luminal B. Reduced folate carrier (RFC1) G80A (OR: 2.92, 95% CI: 1.22-6.97) and methionine synthase (MTR) A2756G (OR: 4.71, 95% CI: 1.66-13.31) polymorphisms were associated with LuminA-HH subtype while MTHFR C677T showed association with HER-enriched (OR: 30.41, 95% CI: 6.47-142.91). Cytosolic serine hydroxymethyltransferase (cSHMT) conferred protection against basal-like breast cancer (OR: 0.47, 95% CI: 0.22-0.98). HER-enriched and basal-like subtypes showed positive association with familial breast cancer and inverse association with plasma folate. Hyperhomocysteinemia was observed in Luminal B and basal-like subtypes. Multiple linear regression models of aberrant one-carbon metabolism were found to be moderate predictors of breast cancer grade (area under the receiver operating characteristic curve, C = 0.72, 95% CI: 0.58-0.87, P = 0.008). To conclude, aberrations in one-carbon metabolism predict the subtype of breast cancer and disease progression.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, Andhra Pradesh, India.
authors.forename: Shaik Mohammad
authors.initials: SM
authors.lastname: Naushad
authors.forename: Addepalli
authors.initials: A
authors.lastname: Pavani
authors.forename: Yedluri
authors.initials: Y
authors.lastname: Rupasree
authors.forename: Shree
authors.initials: S
authors.lastname: Divyya
authors.forename: Sripurna
authors.initials: S
authors.lastname: Deepti
authors.forename: Raghunadha Rao
authors.initials: RR
authors.lastname: Digumarti
authors.forename: Suryanarayana Raju
authors.initials: SR
authors.lastname: Gottumukkala
authors.forename: Aruna
authors.initials: A
authors.lastname: Prayaga
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology*; D002244:Carbon / Q000378:metabolism*; D016022:Case-Control Studies; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics; D006801:Humans; D008593:Menopause; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D004798:Enzymes; D002244:Carbon; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D013940:Thymidylate Synthase; D012696:Glycine Hydroxymethyltransferase; C520541:SHMT protein, human