Atypia and DNA methylation in nipple duct lavage in relation to predicted breast cancer risk.
BACKGROUND
Tumor suppressor gene (TSG) methylation is identified more frequently in random periareolar fine needle aspiration samples from women at high risk for breast cancer than women at lower risk. It is not known whether TSG methylation or atypia in nipple duct lavage (NDL) samples is related to predicted breast cancer risk.


METHODS
514 NDL samples obtained from 150 women selected to represent a wide range of breast cancer risk were evaluated cytologically and by quantitative multiplex methylation-specific PCR for methylation of cyclin D2, APC, HIN1, RASSF1A, and RAR-beta2.


RESULTS
Based on methylation patterns and cytology, NDL retrieved cancer cells from only 9% of breasts ipsilateral to a breast cancer. Methylation of >/=2 genes correlated with marked atypia by univariate analysis, but not multivariate analysis, that adjusted for sample cellularity and risk group classification. Both marked atypia and TSG methylation independently predicted abundant cellularity in multivariate analyses. Discrimination between Gail lower-risk ducts and Gail high-risk ducts was similar for marked atypia [odds ratio (OR), 3.48; P = 0.06] and measures of TSG methylation (OR, 3.51; P = 0.03). However, marked atypia provided better discrimination between Gail lower-risk ducts and ducts contralateral to a breast cancer (OR, 6.91; P = 0.003, compared with methylation OR, 4.21; P = 0.02).


CONCLUSIONS
TSG methylation in NDL samples does not predict marked atypia after correcting for sample cellularity and risk group classification. Rather, both methylation and marked atypia are independently associated with highly cellular samples, Gail model risk classifications, and a personal history of breast cancer. This suggests the existence of related, but independent, pathogenic pathways in breast epithelium.
Euhus
David M
DM
E6.222, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9155, USA. david.euhus@utsouthwestern.edu
Bu
Dawei
D
Ashfaq
Raheela
R
Xie
Xian-Jin
XJ
Bian
Aihua
A
Leitch
A Marilyn
AM
Lewis
Cheryl M
CM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001826:Body Fluids; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D006801:Humans; D008875:Middle Aged; D009558:Nipples; D011237:Predictive Value of Tests; D011379:Prognosis; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012306:Risk; D007507:Therapeutic Irrigation; D025521:Tumor Suppressor Proteins / Q000235:genetics
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D016207:Cytokines; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta