Multi-disciplinary research team discovers that a gene MED12 is frequently altered in fibroadenomas.
Fibroadenomas are the most common breast tumours in women under 30. In latest research study, published in the Nature Genetics, scientists from the National Cancer Centre Singapore, Duke-NUS Graduate Medical School Singapore, and Singapore General Hospital have made a seminal breakthrough in understanding of the molecular basis of fibroadenoma. They showed that 59% of breast fibroadenomas contain somatic mutations in exon 2 of MED12. This mutation pattern is shared with another female-specific benign tumour, uterine leiomyoma.
In their study, the researchers performed first exome sequencing of eight fibroadenomas with matching whole-blood samples. It revealed recurrent somatic mutations solely in MED12. Targeted sequencing of an additional 90 fibroadenomas confirmed highly frequent MED12 exon 2 mutations (59%) that are probably somatic, with 71% of mutations occurring in codon 44.
By using laser capture microdissection, the researchers showed that MED12 fibroadenoma mutations are present in stromal but not epithelial mammary cells. Expression profiling of MED12-mutated and wild-type fibroadenomas revealed that MED12 mutations are associated with dysregulated oestrogen signaling and extracellular matrix organisation.
Furthermore, the fibroadenoma MED12 mutation spectrum is nearly identical to that of previously reported MED12 lesions in uterine leiomyoma, but not those of other tumours. The authors concluded that benign tumours of the breast and uterus, both of which are key target tissues of oestrogen, may thus share a common genetic basis underpinned by highly frequent and specific MED12 mutations.
Worldwide, it is estimated that millions of women are diagnosed with fibroadenoma annually. Frequently discovered in clinical work-ups for breast cancer diagnosis and during routine breast cancer screening, clinicians often face of challenge of distinguishing fibroadenomas from breast cancer. To facilitate this diagnostic question, the team embarked on a study to identify if there are any genetic abnormalities in fibroadenomas that may be used to differentiate them.
According to Prof. Tan Puay Hoon, study co-author: "It is amazing that these common breast tumours can be caused by such a precise disruption in a single gene. Our findings show that even common diseases can have a very exact genetic basis. Importantly, now that we know the cause of fibroadenoma, this research can have many potential applications."
Prof Patrick Tan added, "For example, measuring the MED12 gene in breast lumps may help clinicians to distinguish fibroadenomas from other types of breast cancer. Drugs targeting the MED12 pathway may also be useful in patients with multiple and recurrent fibroadenomas as this could help patients avoid surgery and relieve anxiety."
The team's findings have also deepened the conceptual understanding of how tumours can develop. Unlike breast cancers, where the genetic abnormalities arise from the epithelial cells, the scientists showed that the pivotal MED12 mutations in fibroadenomas are found in the stromal cells.
Associate Prof. Steve Rozen said, "Stromal cells function to provide a supportive tissue around organs, and in breast cancers, are typically thought of as uninvolved or at least secondary bystanders in tumour formation. Our study shows that far from that, fibroadenomas and possibly other tumours may actually arise from genetic lesions in stromal cells. Targeting such stromal cells may be an important avenue for therapy in the future."
The fact that MED12 mutations are shared, highly frequent, and specific to fibroadenomas and uterine fibroids strongly attests to a role for abnormal responses to female hormones in development of these tumours.
The scientists are already planning further studies to explore this possibility by investigating the role of MED12 in other categories of breast tumours.
The study also involved investigators from the Cancer Science Institute of Singapore, Genome Institute of Singapore, A*STAR, and National University Hospital. According to Prof Teh Bin Tean, the study's success was only possible due to a multi-institutional, multi-disciplinary collaboration centred on the concept of team science. The Breast Research Group at Outram leverages on the diverse expertise of scientists and clinicians coming from fields such as molecular biology, bioinformatics, pathology, breast surgery and oncology.
Funding for this work was provided by the Singapore National Medical Research Council, the Singapore Millennium Foundation, the Lee Foundation, the Tanoto Foundation, the National Cancer Centre Singapore's NCC Research Fund, the Duke-NUS Graduate Medical School, the Cancer Science Institute, Singapore and the Verdant Foundation, Hong Kong.
Lim WK, Ong CK, Tan J, et al. Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma. Nature Genetics 2014; Jul 20. doi: 10.1038/ng.3037. [Epub ahead of print]