RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families
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RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families. / Larsen, Martin J; Thomassen, Mads; Tan, Qihua; Lænkholm, Anne-Vibeke; Bak, Martin; Sørensen, Kristina P; Andersen, Mette Klarskov; Kruse, Torben A; Gerdes, Anne-Marie.
I: B M C Medical Genomics, Bind 7, 2014, s. 9.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families
AU - Larsen, Martin J
AU - Thomassen, Mads
AU - Tan, Qihua
AU - Lænkholm, Anne-Vibeke
AU - Bak, Martin
AU - Sørensen, Kristina P
AU - Andersen, Mette Klarskov
AU - Kruse, Torben A
AU - Gerdes, Anne-Marie
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - BRCA1 Protein
KW - BRCA2 Protein
KW - Breast Neoplasms
KW - Cluster Analysis
KW - DNA Methylation
KW - Epigenesis, Genetic
KW - Family
KW - Female
KW - Gene Expression Profiling
KW - Genes, Neoplasm
KW - Genetic Predisposition to Disease
KW - Humans
KW - Male
KW - Middle Aged
KW - Pedigree
KW - Principal Component Analysis
KW - Promoter Regions, Genetic
KW - RNA, Messenger
KW - RNA, Neoplasm
KW - Receptors, Estrogen
U2 - 10.1186/1755-8794-7-9
DO - 10.1186/1755-8794-7-9
M3 - Journal article
C2 - 24479546
VL - 7
SP - 9
JO - BMC Medical Genomics
JF - BMC Medical Genomics
SN - 1755-8794
ER -
ID: 135495615