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Singapore, Duke Scientists Identify Genes Underlying Distinct Group of Breast Tumors: Fibroepithelial Tumors, Benign & Malignant Forms

A team from the SingHealth Duke-NUS Academic Medical Centre, comprising scientists and clinicians from the National Cancer Centre Singapore (NCCS), Singapore General Hospital (SGH), and Duke-NUS Graduate Medical School, has uncovered the genetic landscape of a distinct breast tumor group called fibroepithelial tumors. Their study identified the culprit genes behind the formation and progression of these tumors, potentially improving the accuracy of breast cancer diagnosis and enhancing clinical intervention for patients with such tumors. The study's findings were published online on October 5, 2015 in Nature Genetics. The article is titled “Genomic Landscapes of Breast Fibroepithelial Tumors.” Fibroepithelial tumors are a distinct breast tumor group which includes two tumor types - fibroadenomas and phyllodes tumors. Fibroadenomas are the most common benign breast tumors in women of reproductive age, with thousands of women in Singapore and millions worldwide estimated to be diagnosed with fibroadenomas every year. Only last year, the team identified novel MED12 mutations in the majority of fibroadenomas, a finding that was also reported in Nature Genetics and has since attracted attention and interest worldwide. Now, they have charted the genetic landscape for fibroadenomas, as well as phyllodes tumors, another subtype of fibroepithelial tumors that have both benign and cancerous forms, the latter accounting for about two per cent of breast cancers in Singapore. "Breast cancer is the leading cancer affecting women in Singapore. By shedding light on the genetic landscape of fibroepithelial breast tumours, we can delve deeper [more deeply] into how they are formed, their possible progression into cancer, and determine how to manage them," said Professor Teh Bin Tean, Deputy Director (Research), NCCS, and a co-principal investigator (PI) of the study. Currently, distinguishing fibroadenomas from phyllodes tumors can be challenging to clinicians. The tumors can also progress from benign into malignant forms, and recur even after surgical removal. A deeper understanding of their formation and progression is thus important for the accurate diagnoses and treatment of such tumors, and for breast cancer care.

The team studied 100 fibroepithelial tumors and uncovered the genes responsible for their formation and progression.

Specifically, the scientists performed exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, and observed three distinct somatic mutation patterns.

First, the team frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis.

Second, the scientists found that phyllodes tumors exhibited mutations in FLNA, SETD2, and KMT2D, suggesting a role in driving phyllodes tumor development.

Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors.

IMPACT ON PATIENTS

Understanding the genetic landscape of fibroepithelial breast tumors allows doctors to improve the diagnostic accuracy of breast tumor assessment.

"In pathology, we see challenging cases where fibroadenomas and phyllodes tumours are not clearly distinguishable. The discovery of their causative genes brings hope that we can eventually test for the presence of culprit genes to identify these breast tumor types accurately. Patients can then receive appropriate clinical intervention in a timely manner," said Professor Tan Puay Hoon, Head and Senior Consultant, Department of Pathology, SGH and a co-PI of the study.

Professor Steve Rozen from Duke-NUS' Cancer and Stem Cell Biology Program and a co-PI of the study further explained, "If gene mutations in a patient's breast tumor suggest it may progress from a benign to cancerous form, doctors can then advise patients to have it completely surgically removed to prevent cancer occurrence."

The findings also provide candidate therapeutic targets for fibroepithelial tumors, paving the way for alternative treatment options. Currently, there is no effective therapy for phyllodes tumors apart from surgery.

"This discovery unleashes tremendous potential for the treatment of fibroepithelial breast tumors. Other than surgery, drugs targeting the tumors' gene pathway could help to treat them or prevent recurrence, which is not uncommon among patients with these tumors," said Professor Patrick Tan from the Duke-NUS' Cancer and Stem Cell Biology Programme and a co-PI of the study.

Recently, Professors Tean, Tan and Rozen were recognized with the 2015 President's Science Award (PSA) for their outstanding translational research work in Asian cancer genomics, which includes the team's study on breast tumors. The PSA is one of the highest honours bestowed on exceptional researchers in Singapore for their outstanding contributions to research.

Image shows histology of a subset of phyllodes tumors.

[Press release] [Nature Genetics abstract] [President’s Science and Technology Awards 2015] [President’s Science and Technology Awards 2015 YouTube video]