Lack of HIN-1 methylation in BRCA1-linked and "BRCA1-like" breast tumors.
We recently identified a candidate tumor suppressor gene, HIN-1, that is silenced due to methylation in the majority of sporadic breast carcinomas and is localized to 5q33-qter, an area frequently lost in BRCA1 tumors and thought to harbor a BRCA1 modifier gene. To establish whether germ-line mutations in HIN-1 may influence breast cancer risk, we sequenced the HIN-1 coding region in 10 familial breast cancer patients with positive logarithm of the odds scores of at least one of the markers flanking HIN-1. We also sequenced the HIN-1 coding region in 15 BRCA1 and 35 sporadic breast tumors to determine whether HIN-1 is the target of the frequent 5q loss in BRCA1 tumors. No sequence alterations were found in any of the cases analyzed. However, analysis of HIN-1 promoter methylation status revealed that in striking contrast to sporadic cases, there is a nearly complete lack of HIN-1 methylation in BRCA1 tumors (P < 0.0001). Sporadic breast tumors with a "BRCA1-like" histopathological phenotype also demonstrated significantly lower frequency of HIN-1 promoter methylation (P = 0.01) compared with other cancer types, and there was also a difference among tumors based on their estrogen receptor and HER2 status (P = 0.006), suggesting that HIN-1 methylation patterns are associated with specific breast cancer subtypes.
Krop
Ian
I
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Maguire
Paula
P
Lahti-Domenici
Jaana
J
Lodeiro
Gabriela
G
Richardson
Andrea
A
Johannsdottir
Hrefna Kristin
HK
Nevanlinna
Heli
H
Borg
Ake
A
Gelman
Rebecca
R
Barkardottir
Rosa Björk
RB
Lindblom
Annika
A
Polyak
Kornelia
K
D001943:Breast Neoplasms / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D019398:Genes, BRCA1; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D025521:Tumor Suppressor Proteins
D016207:Cytokines; D004273:DNA, Neoplasm; C434732:SCGB3A1 protein, human; D025521:Tumor Suppressor Proteins