Homologous Recombination Deficiency: Cancer Predispositions and Treatment Implications

Background: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice. Methods: We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing. Results: Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2, whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively. Conclusion: We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results.

Section: Introductionmentioning

confidence: 99%

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Turchiano

Loconte

Nola

et al. 2022

“…As such, pathogenic germline mutations in BRCA genes are associated with heritable cancer syndromes, predisposing to multiple solid tumors, including breast, ovarian, prostate and pancreatic cancer [6,7]. HRD tumor cells are characterized by a striking sensitivity to platinum chemotherapy and PARPi [4,5], but HRD and responsiveness to platinum chemotherapy/PARPi are not solely restricted to BRCA mutant tumors [8]. Mutations in some non-BRCA HR genes are also associated with HRD, although not all non-BRCA HR gene mutations confer the same clinical impact [9].…”

Section: Introductionmentioning

confidence: 99%

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Wattenberg

Reiss

2021

Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.

“…Homologous recombination deficiency (HRD) characterizes a unique set of cancers of various histologic origin leading to increased tumor mutation burden and special sensitivity to immune checkpoint inhibitors or to PARP inhibitors [ 18 ]. A study demonstrated that in breast cancer disseminated brain metastases genomic aberration-based HRD measures are significantly higher in metastases relative to their matched primary tumors suggesting that HR-deficient brain metastases might be more sensitive to PARP inhibitor treatment [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Organ Specific Copy Number Variations in Visceral Metastases of Human Melanoma

Papp

Doma

Gil

et al. 2021

Malignant melanoma is one of the most aggressive skin cancers with high potential of visceral dissemination. Since the information about melanoma genomics is mainly based on primary tumors and lymphatic or skin metastases, an autopsy-based visceral metastasis biobank was established. We used copy number variation arrays (N = 38 samples) to reveal organ specific alterations. Results were partly completed by proteomic analysis. A significant increase of high-copy number gains was found in an organ-specific manner, whereas copy number losses were predominant in brain metastases, including the loss of numerous DNA damage response genes. Amplification of many immune genes was also observed, several of them are novel in melanoma, suggesting that their ectopic expression is possibly underestimated. This “immunogenic mimicry” was exclusive for lung metastasis. We also provided evidence for the possible autocrine activation of c-MET, especially in brain and lung metastases. Furthermore, frequent loss of 9p21 locus in brain metastases may predict higher metastatic potential to this organ. Finally, a significant correlation was observed between BRAF gene copy number and mutant allele frequency, mainly in lung metastases. All of these events may influence therapy efficacy in an organ specific manner, which knowledge may help in alleviating difficulties caused by resistance.