Searching for the 'signature' causes of BRCAness in breast cancer

August 21, 2017, Broad Institute of MIT and Harvard
Credit : Susanna M. Hamilton, Broad Communications

Breast cancer cells with defects in the DNA damage repair-genes BRCA1 and BRCA2 have a mutational signature (a pattern of base swaps—e.g., Ts for Gs, Cs for As—throughout a genome) known in cancer genomics as "Signature 3." But not all breast tumor cells exhibiting Signature 3 have BRCA1 or BRCA2 mutations. Therefore, some consider Signature 3 a biomarker for "BRCAness," a sign of a breakdown in BRCA-related DNA repair (a process called homologous recombination, or HR) in general and not BRCA damage in particular.

The question is, what else might deactivate HR and give rise to Signature 3? And beyond that, might Signature 3 have a role in the clinic?

To find out, an international team led by Paz Polak, Jaegil Kim, Lior Braunstein, and Gad Getz of the Broad Institute's Cancer Program and William Foulkes of McGill University reanalyzed data from nearly 1,000 tumors collected by The Cancer Genome Atlas (TCGA). Their findings, reported in Nature Genetics, hint that mutational signatures like Signature 3 might fuel a precision medicine approach that uses a tumor's full scope of mutations to guide risk and , instead of focusing on individual genes.

Among the breast tumors exhibiting Signature 3, the researchers found that:

  1. Tumors with germline (inherited) or somatic (acquired) BRCA1 or BRCA2 mutations were overwhelmingly positive for Signature 3. So too were tumors with in PALB2, a gene that works in concert with BRCA1 and BRCA2.
  2. Defects in ATM or CHEK2 (two genes that alert the cell to DNA damage, and which can harbor breast cancer risk-raising germline variants) were not linked to Signature 3.
  3. Expression of RAD51C (another BRCA1/2 partner) was epigenetically blocked in several tumors. This hitherto-unrecognized HR dysfunction mechanism was far more common in basal-like breast tumors from younger African-American women in the dataset than in those from white women, as was epigenetic BRCA1 silencing (a known Signature 3 driver). The reverse was true for mutation-based drivers.

And what of Signature 3's clinical utility? The team found that they could combine the signature's presence or absence in with other data to classify rare BRCA1 and BRCA2 mutations as harmful or not, a finding they noted needs to be investigated further. The researchers also suggested that Signature 3 might one day factor into treatment decisions for women with breast cancer, or help guide development of future "BRCAness"-targeting therapies.

Explore further: Genetic predisposition to breast cancer due to non-brca mutations in ashkenazi Jewish women

More information: Paz Polak et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer, Nature Genetics (2017). DOI: 10.1038/ng.3934

Related Stories

Genetic predisposition to breast cancer due to non-brca mutations in ashkenazi Jewish women

July 20, 2017
Genetic mutations in BRCA1 and BRCA2 increase the risk of breast and ovarian cancer in Ashkenazi Jewish women. A new article published by JAMA Oncology examines the likelihood of carrying another cancer-predisposing mutation ...

One in five breast cancer patients could benefit from existing treatment, genetic study reveals

March 13, 2017
Researchers from the Wellcome Trust Sanger Institute and their collaborators have discovered that a greater number of breast cancers are genetically similar to rarer cases with faulty BRCA1 or BRCA2 genes. The results published ...

New test predicts the risk of non-hereditary breast cancer

June 27, 2014
A simple blood test is currently in development that could help predict the likelihood of a woman developing breast cancer, even in the absence of a high-risk BRCA1 gene mutation, according to research published in the open ...

Researchers discover BRCA1 gene is key for blood forming stem cells

January 24, 2017
Researchers at from the Harold C. Simmons Comprehensive Cancer Center have found that the BRCA1 gene is required for the survival of blood forming stem cells, which could explain why patients with BRCA1 mutations do not have ...

Changes in gene contribute independently to breast and ovarian cancer

January 31, 2017
Defects in a key gene - long thought to drive cancer by turning off the protection afforded by the well-known BRCA genes - spur cancer growth on their own, according to a study led by researchers from NYU Langone Medical ...

BRCA1 mutations in breast and ovarian cancer can predict treatment resistance

July 25, 2016
Mutations in the BRCA1 gene are one of the most common risk factors for breast and ovarian cancers. Although tumors that harbor BRCA1 mutations initially respond well to cancer treatments, many tumors eventually become less ...

Recommended for you

New therapeutic opportunity for the treatment of resistant malignant melanoma

June 21, 2018
A team of researchers led by Dr. Pierre Close, WELBIO researcher at the ULiège GIGA Institute and Dr. Francesca Rapino has uncovered a new therapeutic opportunity in the treatment of malignant melanoma that has acquired ...

Novel therapy makes oxidative stress deadly to cancer

June 21, 2018
Oxidative stress can help tumors thrive, but one way novel cancer treatments work is by pushing levels to the point where it instead helps them die, scientists report.

Biologists discover how pancreatic tumors lead to weight loss

June 20, 2018
Patients with pancreatic cancer usually experience significant weight loss, which can begin very early in the disease. A new study from MIT and Dana-Farber Cancer Institute offers insight into how this happens, and suggests ...

Researchers find 11 genes responsible for the spread of cancer

June 20, 2018
A groundbreaking discovery by University of Alberta researchers has identified previously-unknown therapeutic targets that could be key to preventing the spread of cancer.

'Kiss of death' cancer: How computational geeks may have uncovered a therapy for a deadly disease

June 19, 2018
It's called the 'kiss of death'. Triple negative breast cancer has no targeted drug therapy and, as such, the only hope for these patients is chemotherapy. Triple negative breast cancer is aggressive and deadly. Patients ...

Ovarian cancer cells switched off by 'unusual' mechanism

June 19, 2018
Scientists at the Ovarian Cancer Action Research Centre at Imperial College London have discovered a mechanism that deactivates ovarian cancer cells.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.