RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families.
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.
Department of Clinical Genetics, Odense University Hospital, Sdr, Boulevard 29, Odense 5000, Denmark. martin.larsen@rsyd.dk.
Martin J
MJ
Larsen
Mads
M
Thomassen
Qihua
Q
Tan
Anne-Vibeke
AV
Lænkholm
Martin
M
Bak
Kristina P
KP
Sørensen
Mette Klarskov
MK
Andersen
Torben A
TA
Kruse
Anne-Marie
AM
Gerdes
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D016000:Cluster Analysis; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005190:Family; D005260:Female; D020869:Gene Expression Profiling; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D025341:Principal Component Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen