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Therapeutic Implications of DNA Repair Discoveries in Patients With Homologous Recombination Deficiencies


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Long-molecule scars may help identify patients with BRCA1- and BRCA2-deficient cancer types, according to a recent study published by Setton et al in Nature.

Background

Once DNA is damaged by toxins, radiation, or normal cell division, human cells must continually fix DNA breaks to survive. When cells are unable to repair their DNA effectively, mutations can occur that lead to cancer.

Most cells rely on homologous recombination (HR), which uses proteins called BRCA1 and BRCA2 for accurate DNA repair. Those born with BRCA gene mutations, however, often develop breast cancer and ovarian cancer. BRCA mutations and HR-related issues have recently been found to occur in pancreatic cancer and prostate cancer as well.

As a result, identifying patients with HR-deficient cancer types has become a priority—in part because these cancer cells may be vulnerable to targeted therapies that break their DNA. To detect patients with HR deficiencies, standard lab tests look for scars in the DNA of cancer cells, which occur when sloppy back-up repair processes are used instead of HR to create specific mutation patterns.

Although accurate scar diagnoses enable more tailored treatments, researchers have been puzzled by the subtlety of the scars found in HR-deficient cancer types. Such scars create very small typos in the DNA sequence that are invisible under the microscope. However, HR-deficient cells may show dramatic structural rearrangements in chromosomes that are visible by microscopy.

Study Methods and Results

In this study, the researchers applied new genome graph techniques to detect massive structural DNA changes that rearrange, copy, and delete large sections of chromosomes. They also analyzed DNA molecules 100 times longer than those normally measured in cancer analyses.

After applying these methods, the researchers identified a new scar type seen in HR deficiency called reciprocal pairs. By analyzing thousands of cancer genomes, they demonstrated that when HR fails, reciprocal pair scars may create specific chromosomal changes visible by microscopy and that better explain the biology of HR-deficient cells.

"The long molecules tell us that these scars come from two backup repair mechanisms—homology-independent replication restart and single strand annealing—that may keep HR-deficient cancer cells alive," explained co–senior study author Marcin Imieliński, MD, PhD, Director of Cancer Genomics at the Perlmutter Cancer Center and an attending pathologist at New York University Langone Health. "Blocking the mechanisms may represent new ways to treat these cancers,” he emphasized.

The researchers noted that although their new techniques require the use of whole-genome sequencing, the cost of the technique is currently decreasing. The researchers hope it may soon be practical to use their approach to find more patients with HR deficiencies and better match them with targeted therapies.

Disclosure: For full disclosures of the study authors, visit nature.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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