DNA can be damaged by toxins, radiation, or even the normal process of cell division. In order to survive, human cells must constantly repair these DNA damages. In cells that cannot repair DNA efficiently, changes called mutations can occur, which can contribute to the development of cancer.
Most cells use a system known as homologous recombination (HR) to repair DNA. This process involves the proteins BRCA1 and BRCA2. However, people born with mutations in the BRCA genes are at increased risk of developing breast and ovarian cancers. BRCA mutations and HR problems have recently been found to be associated with prostate and pancreatic cancers as well.
Therefore, identifying cancer patients with HR deficiency has become a priority in the medical field. These cancer cells are vulnerable to targeted therapies that affect DNA.
To identify patients with HR deficiency, standard laboratory tests are used that look for signs of “scarring” in the DNA of cancer cells. These scars occur when repair processes use alternative mechanisms instead of homologous recombination to repair mutations.
Although accurate diagnosis of these scars allows better tailoring of treatment, scientists have always been intrigued by the subtlety of these scars found in HR-deficient cancer cells.
Representation of the double helical structure of DNA. The four coding units (A, T, C, G) are color coded pink, orange, purple and yellow. Credit: NHGRI
These scars cause very small errors in the DNA code that are too small to be detected under a microscope. However, HR-deficient cells show dramatic structural changes in the much larger DNA structures called chromosomes, which are visible under a microscope.
To resolve this paradox, Dr. Marcin Imieliński of NYU Langone Health’s Perlmutter Cancer Center and Dr. Simon Powell of Memorial Sloan Kettering Cancer Center (MSKCC) applied “genome graph” techniques, a method for visualizing data genomics. It was developed in the laboratory of Dr. Imieliński. This method has been used to detect significant structural changes in DNA that rearrange, copy and delete large segments of chromosomes.
The study, which was published in the journal Nature on August 16, examined DNA molecules more than a hundred times longer than those normally studied in cancer analyses.
Through these methods, the team of researchers identified a new type of scars called “reciprocal pairs”, which appear in cases of HR deficiency. Analyzing thousands of cancer genomes, the team showed that when the HR mechanism fails, reciprocal pair scars create specific changes at the chromosome level that are visible under a microscope and that better explain the biology of HR-deficient cancer cells.
Dr. Marcin Imieliński, director of the Cancer Genome at the Perlmutter Center and a pathologist at NYU Langone, explained that “the longer molecules reveal to us that these scars come from two backup repair mechanisms that keep HR-deficient cancer cells alive .”
The study authors pointed out that these new techniques require whole-genome sequencing, and with decreasing costs, this new approach could become useful for identifying HR-deficient patients who could benefit from targeted therapies.
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2023-08-22 20:43:03
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