Interest in therapies that target DDR genes has increased since 2015, when basic science in this area won the Nobel Prize in Chemistry.
Interest in DNA damage repair (DDR) genes and their role in cancer has increased since 2015, when work in this area won the Nobel Prize in Chemistry. The sheer number of DDR genes—more than 400 are associated with DDR—and the various mechanisms that link DNA repair and DDR signaling proteins to both germline and somatic mutations offer multiple research possibilities.
So, which treatments which will help which types of cancers? A study presented last week during the American Association of Cancer Research (AACR) annual meeting offers a road map, as investigators from EMD Serono Research and Development Institute, Foundation Medicine, and Merck examined 35 of the most common DDR genes across the FoundationCORE database, which includes more than 300,000 genomic profiles.
DNA damage repair refers to processes in which a cell corrects damage to the molecules that pass along a person’s genetic code. Certain types of DDR can lead to cancer if the repair pathways become disrupted or through increased levels of replication stress. Environmental factors are known to trigger DDR.
Fortunately, recent research has also uncovered ways in which these DDR alterations can be disrupted, especially with treatments such as immunotherapy or poly ADP ribose polymerase (PARP) inhibitors. The study presented at AACR sought to map out the most common DDR genes across advanced solid tumor cancers, offering a host of new opportunities to improve outcomes.
According to the abstract the genomic alterations studied included not only the DDR genes, but also complex biomarkers such as tumor mutation burden (TMB), genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status, and PD-L1 expression. The study found that DDR gene alterations are common and unevenly distributed across cancer types; this study included breast, ovarian, colorectal, esophagus, biliary track, gastric, head and neck, pancreas, melanoma, lung, bladder, and prostate cancer.
As expected, TP53 was the most frequently altered DDR gene across the various cancers (59%). Other genes found in more than 1% of cancers were ARID1A (9%), ATM (4%), SMARCA4 (3%), MDM2 (3%), BRCA2 (3%), BRCA1 (2%), CHK2 (2%), MUTYH (2%). The remaining DDR genes were rarely altered.
With TP53 excluded from the analysis, bladder cancer was most likely to have cases with mutations in DDR genes at 46.59%, while other cancers have rates ranging between 20% and 40%. Researchers are continuing their analysis of the relative distribution of TMB, MSI, gLOH and PD-L1 expression by tumor type and their connection with DDR genomic alterations.
The data analysis is just the beginning, the researchers said
“We systematically analyzed somatic alterations using the Foundation Medicine comprehensive genomic database and provide a comprehensive molecular profiling of DDR deficiencies in advanced solid tumors,” they wrote in the abstract. “It is anticipated that this data will collectively contribute to identify molecularly defined tumor subsets, where single and/or combination therapies such as DDR inhibitors, immunotherapies, targeted therapies etc., may result in increased clinical benefit for patients with cancer.”
Wang D, Elenbaas B, Murugesan K, et al. Comprehensive molecular profiling of DNA damage response (DDR) deficiencies in advanced solid tumors using a real-world genomic database. Presented at the 2021 American Association of Cancer Research Annual Meeting. Abstract 2062; April 10, 2021.