Prevalence of homologous recombination biomarkers in multiple tumor types: an observational study
Creators: name: Chen, Cai
name: Dettman, Elisha J
name: Zhou, Wei
name: Gozman, Alexander
name: Jin, Fan
name: Lee, Liam C
name: Ren, Yixin
name: Zhou, Heng
name: Cristescu, Razvan
name: Shao, Changxia
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Pharmacology
subject: Biotechnology
subject: Biological Sciences not elsewhere classified
subject: Cancer
subject: Infectious Diseases
subject: FOS: Health sciences

description: <b>Aim:</b> To determine the prevalence of deleterious mutations in <i>BRCA1</i> and <i>BRCA2</i> and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of <i>BRCA1</i>, <i>BRCA2</i> and other HRR gene mutations in multiple solid tumor types. <b>Patients &amp; methods:</b> This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. <b>Results:</b> Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious <i>BRCA1/2</i> mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%–26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6–34.4%) across all tumor types. <b>Conclusion:</b> The prevalence of mutations varied significantly depending on the type of tumor. The integrity of the human genome is maintained via multiple pathways of DNA repair, one of the most important of which is homologous recombination repair (HRR), which uses a sister chromatid as a template for high-fidelity restoration of altered DNA sequences. This study aimed to determine the prevalence of deleterious mutations, i.e., changes in the genetic code that interfere with proper cellular function, in the breast cancer genes <i>BRCA1</i> and <i>BRCA2</i> and in 13 other genes involved in HRR in various types of solid tumors in patients with advanced or metastatic cancer. The researchers found that 4.7% of tumor samples had <i>BRCA1/2</i> mutations, 13.6% had mutations in any of the HRR genes and 20.6% had genomic loss of heterozygosity (gLOH) of at least 16% i.e., loss of sections of chromosomes affecting 16% or more of the genome. <i>BRCA1/2</i> mutations were most common in ovarian cancer (13.1%), prostate cancer (9.3%), breast cancer (8.2%) and pancreatic cancer (4.9%). Prevalence for mutations in HRR genes ranges from 2.4 to 26.0% and gLOH ≥16% ranged from 2.6 to 34.4% depending on the tumor type. In conclusion, the prevalence of mutations in the <i>BRCA1/2</i> genes, HRR genes and gLOH ≥16% varied widely across 15 tumor types. Among 9457 patients across 15 solid tumor types, we found that 4.7% had <i>BRCA1/2</i> mutations, 13.6% had mutations in homologous recombination repair genes and 20.6% had gLOH ≥16%. The prevalence of mutations varied by tumor type. The prevalence of mutations in homologous recombination repair (HRR) genes and of genomic loss of heterozygosity (gLOH) and the allelic and hereditary status of these mutations across solid tumor types are not well described. This study reports the prevalence of mutations in <i>BRCA1/2</i> and in 13 other HRR genes and of gLOH across 15 tumor types, including tumor types beyond those more commonly associated with these biomarkers. Almost 5% of tumor samples had <i>BRCA1/2</i> mutations, 14% had mutations in any of the HRR genes and 21% had a high prevalence of gLOH (gLOH ≥16%). The highest prevalences of were <i>BRCA1/2</i> mutations in ovarian (13.1%), prostate (9.3%), breast (8.2%) and pancreatic (4.9%) cancers. The prevalence of <i>BRCA1/2</i> mutations in mesothelioma, bladder cancer, endometrial cancer and gastric cancer were not negligible. Among tumors where biallelic status was determined, the biallelic proportions of <i>BRCA1/2</i> mutations were 95% in prostate, 86% in ovarian, 83% in breast, 77% in pancreatic cancer and from 23% (gastric cancer) to 38% (bladder cancer) in other tumor types. Among tumors where heritable status was determined, germline <i>BRCA1/2</i> mutations predominated in pancreatic and breast cancers, whereas somatic mutations were the majority in ovarian and most of the other tumor types. Across all tumor types, the proportion of gLOH ≥16% was highest in those with biallelic mutations of <i>BRCA1</i>, <i>BRCA2</i> and <i>PALB2</i>. The prevalence of mutations in HRR genes varied considerably across tumor types. Evaluation of HRR gene alterations and gLOH may enable identification of tumors that are susceptible to drugs that act by causing double-strand DNA breaks.