RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families

BMC Medical Genomics

Anne-Marie Gerdes¹  Torben A Kruse³  Mette Klarskov Andersen¹  Kristina P Sørensen³  Martin Bak⁴  Anne-Vibeke Lænkholm⁵  Qihua Tan²  Mads Thomassen³  Martin J Larsen³ 

[1] Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark;Human Genetics, Clinical Institute, University of Southern Denmark, Odense, Denmark;Department of Pathology, Odense University Hospital, Odense, Denmark;Slagelse Hospital, Department of Pathology, Slagelse, Denmark

关键词: Promoter methylation;    Molecular subtypes;    Microarray analysis;    Gene expression analysis;    non-BRCA1/2;    RNA profiling;    Hereditary breast and ovarian cancer syndrome;   

Others  :  797123
DOI  :  10.1186/1755-8794-7-9

 received in 2013-10-23, accepted in 2014-01-24,  发布年份 2014

【 摘 要 】

Background

In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar underlying pathophysiological mechanisms. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer patients within the same family.

Methods

In the current study we analyzed a collection of 70 frozen breast tumor biopsies from a total of 58 families by global RNA profiling and promoter methylation analysis.

Results

We show that distinct functional subgroupings, similar to the intrinsic molecular breast cancer subtypes, exist among non-BRCA1/2 breast cancers. The distribution of subtypes was markedly different from the distribution found among BRCA1/2 mutation carriers. From 11 breast cancer families, breast tumor biopsies from more than one affected family member were included in the study. Notably, in 8 of these families we found that patients from the same family shared the same tumor subtype, showing a tendency of familial aggregation of tumor subtypes (p-value = 1.7e-3). Using our previously developed BRCA1/2-signatures, we identified 7 non-BRCA1/2 tumors with a BRCA1-like molecular phenotype and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found.

Conclusions

Our finding indicates involvement of hereditary factors in non-BRCA1/2 breast cancer families in which family members may carry genetic susceptibility not just to breast cancer but to a particular subtype of breast cancer. This is the first study to provide a biological link between breast cancers from family members of high-risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly homogeneous subtypes in order to search for new high penetrance susceptibility genes.

【 授权许可】

   
2014 Larsen et al.; licensee BioMed Central Ltd.

【 图 表 】

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