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Despite the rising knowledge about genes involved in the formation and occurrence of cancers, only a limited amount of genes has been identified to be involved in hereditary cancers, e.g. BRCA1, BRCA2. However, only up to 45% of all hereditary breast and ovarian cancer patients show mutations in BRCA1 or BRCA2. Thus, there is still a need for new markers assessing the predisposition for cancers.
The present invention provides a novel susceptibility gene for hereditary cancers. RAD51C, which encodes for a protein involved in DNA repair, has been found to be mutated in families with breast and ovarian cancer, but not in healthy control subjects.
In addition, the patients were all selected from pedigrees negative for mutations of BRCA1 and BRCA2 to particularly identify genetic mutations causing a cancer predisposition independently of already known determinants. All analyzed mutations were identified as mono-allelic germline mutations.
Besides gynecological cancers, mutations of RAD51C were also detected in patients suffering from head and neck squamous cell carcinomas (HNSSC).
Thus, the presence of mutations in RAD51C is associated with an increased predisposition of developing cancer and positions RAD51C as a high-risk cancer susceptibility gene.
Furthermore, an abnormal RAD51C gene status correlates with an increased probability for response to a DNA-damaging therapeutic agent and therefore represents an ideal companion diagnostic.
RAD51C is one of the five paralogs of the RAD51 recombinase and an essential DNA repair protein that is required for error-free repair of DNA double strand breaks (1, 2). Other well established cancer susceptibility genes in the same homologous recombination (HR) pathway are BRCA1, BRCA2, BRIP1, and PALB2 (3).
Bi-allelic germline loss-of-function mutations in RAD51C cause Fanconi anemia, a rare childhood disorder (4). Monoallelic germline mutations are associated with a significantly increased lifetime risk for familiar breast, ovarian and other cancers (4-6). In familiar as well as sporadic ovarian cancer patients, RAD51C is the third most frequently mutated gene - after BRCA1/2 (7). Importantly, loss-of-heterozygosity (LOH) of the wild-type allele occurs in at least 80% of tumors (5). It was reported that 3% of epithelial ovarian cancers had RAD51C promoter methylation, the second highest after BRCA1 methylation, and these tumors had a higher HRD score which is associated with improved survival (8).
Cells deficient for RAD51C by any means are hypersensitive for DNA-crosslinking agents (e.g. cis/carboplatin, mitomycin C) (4), PARP inhibitors (e.g. olaparib) (4, 9) and TOPO I inhibitors (4), thus rendering RAD51C deficient tumor cells eligible for synthetic lethality approaches.
Overview and Current Use of RAD51C
• Measures to understand the genomic make-up of an individual’s cancer cells are anticipated to play an increasingly important role for risk-adapted personalized treatment (e.g. companion diagnostics for PARP inhibitors) and also surveillance strategies, thereby ultimately improving the prognosis for the patient.
• Next generation sequencing-based approaches are increasingly accepted by professional societies and health care systems as appropriate diagnostic approaches to identify individuals with germline and/or somatic mutation(s) in cancer risk genes.
• RAD51C is an established cancer susceptibility gene.
• Myriad Genetics included RAD51C (in addition to BRCA1 and 2) in their homologous Recombination Deficiency (HRD) test which is currently in the validation phase.
• The proprietors offer EP 11 713 793.5, US 13/640,117 and CA 2,795,880 (derived from PCT/EP2011/055651, published as WO2011/124725 A1) as well as
EP 10 159 524.7 (priority application) for exclusive license.
• The disclosure and the claims currently pending are concentrated in three areas:
1. the diagnostic use of loss-of-function germ-line mutations in RAD51C as cancer susceptibility factor for inherited and sporadic breast, ovarian and head/neck cancers
2. the diagnostic use of RAD51C loss-of-function (either by mutations, splice defects, promoter methylations, microRNAs, protein abnormalities) in tumor cells of breast, ovarian and head/neck cancer patients
3. the use of RAD51C loss-of-function information in tumor cells for treatment stratification, e.g. for PARP or TOPO I inhibitors
• The grant of a European patent based on the priority application EP 10 159 524.7 is currently postponed to allow a potential licensee to decide on claim structure and claim language as well as on relevant European countries.
1. J. Thacker, The RAD51 gene family, genetic instability and cancer. Cancer Lett 219, 125 (Mar 10, 2005).
2. A. J. Deans, S. C. West, DNA interstrand crosslink repair and cancer. Nat Rev Cancer 11, 467 (2011).
3. A. D. D'Andrea, Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med 362, 1909 (May 20, 2010).
4. F. Vaz et al., Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42, 406 (May, 2010).
5. A. Meindl et al., Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42, 410 (May, 2010).
6. K. Scheckenbach et al., RAD51C--A new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC). Oral Oncol 50, 196 (Mar, 2014).
7. K. P. Pennington, E. M. Swisher, Hereditary ovarian cancer: Beyond the usual suspects. Gynecol Oncol 124, 347 (Feb, 2012).
8. V. Abkevich et al., Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107, 1776 (Nov 6, 2012).
9. A. Min et al., RAD51C-deficient cancer cells are highly sensitive to the PARP inhibitor olaparib. Mol Cancer Ther 12, 865 (Jun, 2013).
An invention of the University Hospital Cologne (UKK), the Heinrich-Heine-University Duesseldorf and Prof. Helmut Hanenberg.