The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer.

Göran B Jönsson, Johan Staaf, Johan Vallon-Christersson, Markus Ringnér, Sofia Gruvberger, Lao Saal, Karolina Holm, Cecilia Hegardt, Adalgeir Arason, Rainer Fagerholm, Camilla Olsson, Dorthe Grabau, Ellinor Johnsson, Kristina Lövgren, Linda Magnusson, Paivi Heikkilä, Bjarni A Agnarsson, Oskar Th Johannsson, Per Malmström, Mårten FernöHåkan Olsson, Niklas Loman, Heli Nevanlinna, Rosa Bjork Barkardottir, Åke Borg

Research output: Contribution to journalArticlepeer-review

Abstract

Breast tumors from BRCA1 germ line mutation carriers typically exhibit features of the basal-like molecular subtype. However, the specific genes recurrently mutated as a consequence of BRCA1 dysfunction have not been fully elucidated. In this study, we utilized gene expression profiling to molecularly subtype 577 breast tumors, including 72 breast tumors from BRCA1/2 mutation carriers. Focusing on the RB1 locus, we analyzed 33 BRCA1-mutated, 36 BRCA2-mutated and 48 non-BRCA1/2-mutated breast tumors using a custom-designed high-density oligomicroarray covering the RB1 gene. We found a strong association between the basal-like subtype and BRCA1-mutated breast tumors and the luminal B subtype and BRCA2-mutated breast tumors. RB1 was identified as a major target for genomic disruption in tumors arising in BRCA1 mutation carriers and in sporadic tumors with BRCA1 promoter-methylation, but rarely in other breast cancers. Homozygous deletions, intragenic breaks, or microdeletions were found in 33% of BRCA1-mutant tumors, 36% of BRCA1 promoter-methylated basal-like tumors, 13% of non-BRCA1 deficient basal-like tumors, and 3% of BRCA2-mutated tumors. In conclusion, RB1 was frequently inactivated by gross gene disruption in BRCA1-related hereditary breast cancer and BRCA1-methylated sporadic basal-like breast cancer, but rarely in BRCA2-hereditary breast cancer and non-BRCA1-deficient sporadic breast cancers. Together, our findings demonstrate the existence of genetic heterogeneity within the basal-like breast cancer subtype that is based upon BRCA1-status.
Original languageEnglish
Pages (from-to)4028-4036
JournalCancer Research
Volume72
Issue number16
DOIs
Publication statusPublished - 2012

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Division of Clinical Genetics (013022003), Division of Hematology and Transfusion Medicine (013041100), Oncology, MV (013035000), Pathology, (Lund) (013030000)

Subject classification (UKÄ)

  • Cancer and Oncology

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