CpG island tumor suppressor promoter methylation in non-BRCA-associated early mammary carcinogenesis.
BACKGROUND
Only 5% of all breast cancers are the result of BRCA1/2 mutations. Methylation silencing of tumor suppressor genes is well described in sporadic breast cancer; however, its role in familial breast cancer is not known.


METHODS
CpG island promoter methylation was tested in the initial random periareolar fine-needle aspiration sample from 109 asymptomatic women at high risk for breast cancer. Promoter methylation targets included RARB (M3 and M4), ESR1, INK4a/ARF, BRCA1, PRA, PRB, RASSF1A, HIN-1, and CRBP1.


RESULTS
Although the overall frequency of CpG island promoter methylation events increased with age (P<0.0001), no specific methylation event was associated with age. In contrast, CpG island methylation of RARB M4 (P=0.051), INK4a/ARF (P=0.042), HIN-1 (P=0.044), and PRA (P=0.032), as well as the overall frequency of methylation events (P=0.004), was associated with abnormal Masood cytology. The association between promoter methylation and familial breast cancer was tested in 40 unaffected premenopausal women in our cohort who underwent BRCA1/2 mutation testing. Women with BRCA1/2 mutations had a low frequency of CpG island promoter methylation (15 of 15 women had <or=4 methylation events), whereas women without a mutation showed a high frequency of promoter methylation events (24 of 25 women had 5-8 methylation events; P<0.0001). Of women with a BRCA1/2 mutation, none showed methylation of HIN-1 and only 1 of 15 women showed CpG island methylation of RARB M4, INK4a/ARF, or PRB promoters.


CONCLUSIONS
This is the first evidence of CpG island methylation of tumor suppressor gene promoters in non-BRCA1/2 familial breast cancer.
Vasilatos
Shauna N
SN
Department of Medicine, Duke University Medical Center, Box 2628, Durham, NC 27710, USA.
Broadwater
Gloria
G
Barry
William T
WT
Baker
Joseph C
JC
Lem
Siya
S
Dietze
Eric C
EC
Bean
Gregory R
GR
Bryson
Andrew D
AD
Pilie
Patrick G
PG
Goldenberg
Vanessa
V
Skaar
David
D
Paisie
Carolyn
C
Torres-Hernandez
Alejandro
A
Grant
Tracey L
TL
Wilke
Lee G
LG
Ibarra-Drendall
Catherine
C
Ostrander
Julie H
JH
D'Amato
Nicholas C
NC
Zalles
Carola
C
Jirtle
Randy
R
Weaver
Valerie M
VM
Seewaldt
Victoria L
VL
D044963:Biopsy, Fine-Needle; D001943:Breast Neoplasms / Q000235:genetics*; D016009:Chi-Square Distribution; D018899:CpG Islands / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D016133:Polymerase Chain Reaction; D017697:Premenopause; D011401:Promoter Regions, Genetic / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012306:Risk; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D025521:Tumor Suppressor Proteins / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016207:Cytokines; D011980:Receptors, Progesterone; D018168:Receptors, Retinoic Acid; C434732:SCGB3A1 protein, human; D025521:Tumor Suppressor Proteins; C097314:progesterone receptor B; C082925:retinoic acid receptor beta