RESUMEN

Cancer predisposition syndromes are recognized in about 10% of pediatric malignancies with several genes specifically involved in a subset of pediatric tumors such as DICER1, in pleuropulmonary blastoma, cystic nephroma, and brain sarcomas. By contrast, the role of BRCA1/2 in pediatric cancer predisposition is still under investigation. We present two cases of young first-degree cousins, both carrying a germline BRCA2 variant and developing tumors characterized by somatic DICER1 mutations. Patient 1 presented with a cystic nephroma harboring a somatic DICER1 variant (p.Asp1810Tyr), while patient 2 had a primary intracranial DICER1-mutated sarcoma showing a distinct somatic DICER1 variant (p.Asp1709Glu) as well as biallelic inactivation of TP53 (p.Val173Leu, VAF 91%) and APC (p.Ile1307Lys, VAF 95%) and a pathogenic variant in KRAS (p.Gln61His). Both patients carried the same germline BRCA2 variant (p.Arg2842Cys) of unknown significance. The same variant was found in the mother of patient 2 and in the father of patient 1, who are siblings. A homologous recombination deficiency signature was not identified in any of the two tumors, possibly suggesting a reduction of BRCA2 activity. The association of BRCA2 and DICER1 variants in our cases hints at a potential cooperative role in cancer pathogenesis. Further studies are warranted to elucidate the interplay between BRCA1/2 and DICER1 variants and their implications for cancer predisposition and treatment in pediatric patients.

Asunto(s)

Proteína BRCA2 , ARN Helicasas DEAD-box , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Ribonucleasa III , Humanos , ARN Helicasas DEAD-box/genética , Ribonucleasa III/genética , Proteína BRCA2/genética , Femenino , Masculino , Linaje , Niño

RESUMEN

In 1996, Goggins and colleagues demonstrated the importance of germline BRCA2 pathogenic variants in the development of apparently sporadic pancreatic ductal adenocarcinoma (PDAC). Previously, the group identified homozygous deletion of the 13q region in PDACs, enabling the identification of the BRCA2 gene. This 1996 article first revealed loss of BRCA2, both germline and somatic, as a key driver of PDAC at a time when there was still doubt if PDAC even had an inherited component. Contrary to the prevailing wisdom, not all individuals with inherited pathogenic BRCA2 variants had a family history of cancer. The innovative bedside-to-bench nature of this work revealed that individuals with these variants would be missed if genetic testing was limited only to those meeting the family history criteria. Therefore, Goggins and colleagues advocated that universal genetic testing may be indicated for pancreatic cancer at a time when genetic testing was in its infancy. Twenty-three years later, in 2019, universal testing for pancreatic cancer became standard of care in the United States. Additionally, this work and future-related publications by the Kern Laboratory set the stage for targeting BRCA2 and related DNA repair mutations in pancreatic cancer via a synthetic lethal therapeutic approach. The provocative discussion initiated by this team in this publication is still inspiring the field today. In this seminal publication, Goggins and colleagues profoundly impacted the direction of pancreatic cancer research, leading to a more sophisticated approach to designing earlier detection and precision treatment strategies for pancreatic cancer. See related article by Goggins and colleagues, Cancer Res 1996;56:5360-4.

Asunto(s)

Proteína BRCA2 , Carcinoma Ductal Pancreático , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteína BRCA2/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Pruebas Genéticas/métodos

RESUMEN

PURPOSE: Several international groups have published guidelines to identify low-risk breast cancer (BC) patients who are eligible for partial breast irradiation (PBI). These include the American Society for Radiation Oncology (ASTRO), the European Society for Radiotherapy and Oncology (ESTRO), and ESTRO subgroups such as the Intraoperative radiation (IORT) Task Force and Groupe Européen de Curiethérapie (GEC) -ESTRO. Only ASTRO guidelines recommend against the use of PBI in known carriers of germline pathogenic variants (PVs) in BRCA1/2. The aim of this study was to evaluate the proportion of BC patients, subsequently found to be BRCA1/2 PV carriers who would be eligible for PBI based on clinical-pathologic criteria of the above-mentioned international guidelines. METHODS AND MATERIALS: Data were extracted from the medical records of consecutive BC BRCA1/2 PV carriers treated at a single institution between 2006 and 2023. Data included patient demographics, tumor characteristics, treatment, and disease outcomes. RESULTS: Overall, 498 patients with 518 primary tumors were analyzed. Of these, 282 (12 of them with synchronous bilateral disease) presented with unknown genetic status at diagnosis and formed the study cohort. The median age at diagnosis was 42.7 years (range, 23.8-77.9). Based on the recent ASTRO guidelines (not including conditionally recommended criteria), 17 of 294 (5.8%) of the carriers had tumors that would be eligible for PBI, including 3 Her2-positive tumors and 5 patients diagnosed between ages 40 and 49 years. Using the ESTRO IORT and the ACROP-ESTRO PBI criteria, 9 of 294 (3%) would be eligible, whereas with the GEC-ESTRO low-risk criteria, 31 of 294 (10.5%) of the carriers would be eligible, and their intermediate risk criteria would increase eligibility for PBI by an additional 8.2% (overall 18.7%). CONCLUSIONS: Using clinical-pathologic criteria published in international guidelines, 3% to 18% of BRCA1/2 PV carriers will have tumors eligible for PBI. Therefore, especially in populations who are at high risk for being BRCA1/2 PV carriers, we recommend adhering to stricter guidelines. In our cohort, ASTRO, ESTRO-IORT, and ESTRO PBI had the lowest probability of identifying BRCA1/2 PV carriers as eligible for PBI.

Asunto(s)

Proteína BRCA1 , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Adulto , Persona de Mediana Edad , Proteína BRCA1/genética , Proteína BRCA2/genética , Anciano , Mutación , Heterocigoto

RESUMEN

Importance: Between 5% and 10% of breast cancer cases are associated with an inherited germline pathogenic or likely pathogenic variant (GPV) in a breast cancer susceptibility gene (BCSG), which could alter local and systemic therapy recommendations. Traditional genetic testing criteria misses a proportion of these cases. Objective: To evaluate the prevalence and clinicopathological associations of GPVs in 2 groups of BCSGs among an ethnically diverse cohort of women with newly diagnosed breast cancer. Design, Setting, and Participants: This cross-sectional study, conducted at 3 Montreal hospitals between September 2019 and April 2022, offered universal genetic counseling and testing to all women with a first diagnosis of invasive breast cancer. Women were offered an obligatory primary panel of BRCA1, BRCA2, and PALB2 (B1B2P2) and an optional secondary panel of 14 additional BCSGs. Eligible participants were women 18 years of age or older who received a diagnosis of a first primary invasive breast cancer not more than 6 months before the time of referral to the study. Data were analyzed from November 2023 to June 2024. Results: Of 1017 referred patients, 805 were eligible and offered genetic counseling and testing, and 729 of those 805 (90.6%) consented to be tested. The median age at breast cancer diagnosis was 53 years (range, 23-91 years), and 65.4% were White and of European ancestry. Fifty-four GPVs were identified in 53 patients (7.3%), including 39 patients (5.3%) with B1B2P2 and 15 patients (2.1%) with 6 of the 14 secondary panel BCSGs (ATM, BARD1, BRIP1, CHEK2, RAD51D, and STK11). On multivariable analysis, clinical factors independently associated with B1B2P2-positive status included being younger than 40 years of age at diagnosis (odds ratio [OR], 6.83; 95% CI, 2.22-20.90), triple-negative breast cancer (OR, 3.19; 95% CI, 1.20-8.43), high grade disease (OR, 1.68; 95% CI, 1.05-2.70), and family history of ovarian cancer (OR, 9.75; 95% CI, 2.65-35.85). Of 39 B1B2P2-positive patients, 13 (33.3%) were eligible for poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. Conclusions and Relevance: In this cross-sectional universal genetic testing study of women with newly diagnosed invasive breast cancer, the prevalence of GPVs was 7.3%, with 5.3% of patients testing positive for B1B2P2. Among B1B2P2-women women, one-third were eligible for PARP inhibitors.

Asunto(s)

Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/genética , Neoplasias de la Mama/diagnóstico , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Estudios Transversales , Adulto , Anciano , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Asesoramiento Genético/estadística & datos numéricos , Proteína BRCA1/genética , Proteína BRCA2/genética

RESUMEN

BACKGROUND: The status of BRCA1/2 genes plays a crucial role in the treatment decision-making process for multiple cancer types. However, due to high costs and limited resources, a demand for BRCA1/2 genetic testing among patients is currently unmet. Notably, not all patients with BRCA1/2 mutations achieve favorable outcomes with poly (ADP-ribose) polymerase inhibitors (PARPi), indicating the necessity for risk stratification. In this study, we aimed to develop and validate a multimodal model for predicting BRCA1/2 gene status and prognosis with PARPi treatment. METHODS: We included 1695 slides from 1417 patients with ovarian, breast, prostate, and pancreatic cancers across three independent cohorts. Using a self-attention mechanism, we constructed a multi-instance attention model (MIAM) to detect BRCA1/2 gene status from hematoxylin and eosin (H&E) pathological images. We further combined tissue features from the MIAM model, cell features, and clinical factors (the MIAM-C model) to predict BRCA1/2 mutations and progression-free survival (PFS) with PARPi therapy. Model performance was evaluated using area under the curve (AUC) and Kaplan-Meier analysis. Morphological features contributing to MIAM-C were analyzed for interpretability. RESULTS: Across the four cancer types, MIAM-C outperformed the deep learning-based MIAM in identifying the BRCA1/2 genotype. Interpretability analysis revealed that high-attention regions included high-grade tumors and lymphocytic infiltration, which correlated with BRCA1/2 mutations. Notably, high lymphocyte ratios appeared characteristic of BRCA1/2 mutations. Furthermore, MIAM-C predicted PARPi therapy response (log-rank p < 0.05) and served as an independent prognostic factor for patients with BRCA1/2-mutant ovarian cancer (p < 0.05, hazard ratio:0.4, 95% confidence interval: 0.16-0.99). CONCLUSIONS: The MIAM-C model accurately detected BRCA1/2 gene status and effectively stratified prognosis for patients with BRCA1/2 mutations.

Asunto(s)

Mutación , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Masculino , Proteína BRCA1/genética , Proteína BRCA2/genética , Pronóstico , Persona de Mediana Edad , Supervivencia sin Progresión , Neoplasias Ováricas/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Terapia Molecular Dirigida/métodos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto

RESUMEN

PURPOSE: To support doctors in counselling women with genetic predisposition for breast or gynecologic cancers on endocrine interventions. METHODS: Evidence on the safety of endocrine interventions for fertility treatment, contraception, hormone replacement therapy after risk-reducing salpingo-oophorectomy (RRSO) or treatment of symptoms during peri- and postmenopause was analysed for carriers of probably pathogenic and pathogenic variants in BRCA1 or BRCA2 (BRCA1/2-pV), in other breast and ovarian cancer genes and the Lynch Syndrome. Cancer risks were compared with data on risks for the general population. RESULTS: Data on risk modulation of endocrine interventions in women with genetic predisposition is limited. Ovarian hyperstimulation for fertility treatment may be performed. Oral contraceptives should not be used to reduce ovarian cancer risk in BRCA1/2-pV carriers. Premenopausal BRCA1/2-pV carriers and carriers of pV in Lynch Syndrome genes should be offered hormone replacement therapy (HRT) after RRSO, to prevent diseases caused by estrogen deficiency. CONCLUSION: Effect direction and strength of risk modulation by endocrine interventions is similar to the general population. Participation of individuals at risk in prospective registries is recommended.

Asunto(s)

Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Terapia de Reemplazo de Hormonas/efectos adversos , Terapia de Reemplazo de Hormonas/métodos , Neoplasias de los Genitales Femeninos/genética , Heterocigoto , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Alemania , Proteína BRCA2/genética , Proteína BRCA1/genética

RESUMEN

Ribosomal DNA (rDNA) encodes the ribosomal RNA genes and represents an intrinsically unstable genomic region. However, the underlying mechanisms and implications for genome integrity remain elusive. Here, we use Bloom syndrome (BS), a rare genetic disease characterized by DNA repair defects and hyper-unstable rDNA, as a model to investigate the mechanisms leading to rDNA instability. We find that in Bloom helicase (BLM) proficient cells, the homologous recombination (HR) pathway in rDNA resembles that in nuclear chromatin; it is initiated by resection, replication protein A (RPA) loading and BRCA2-dependent RAD51 filament formation. However, BLM deficiency compromises RPA-loading and BRCA1/2 recruitment to rDNA, but not RAD51 accumulation. RAD51 accumulates at rDNA despite depletion of long-range resection nucleases and rDNA damage results in micronuclei when BLM is absent. In summary, our findings indicate that rDNA is permissive to RAD51 accumulation in the absence of BLM, leading to micronucleation and potentially global genomic instability.

Asunto(s)

ADN Ribosómico , Inestabilidad Genómica , Recombinasa Rad51 , RecQ Helicasas , Recombinasa Rad51/metabolismo , Recombinasa Rad51/genética , ADN Ribosómico/genética , ADN Ribosómico/metabolismo , Humanos , RecQ Helicasas/metabolismo , RecQ Helicasas/genética , Proteína de Replicación A/metabolismo , Proteína de Replicación A/genética , Recombinación Homóloga , Síndrome de Bloom/genética , Síndrome de Bloom/metabolismo , Proteína BRCA2/metabolismo , Proteína BRCA2/genética , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Reparación del ADN

RESUMEN

Importance: Population-based BRCA testing can identify many more BRCA carriers who will be missed by the current practice of BRCA testing based on family history (FH) and clinical criteria. These carriers can benefit from screening and prevention, potentially preventing many more breast and ovarian cancers and deaths than the current practice. Objective: To estimate the incremental lifetime health outcomes, costs, and cost-effectiveness associated with population-based BRCA testing compared with FH-based testing in Canada. Design, Setting, and Participants: For this economic evaluation, a Markov model was developed to compare the lifetime costs and outcomes of BRCA1/BRCA2 testing for all general population women aged 30 years compared with FH-based testing. BRCA carriers are offered risk-reducing salpingo-oophorectomy to reduce their ovarian cancer risk and magnetic resonance imaging (MRI) and mammography screening, medical prevention, and risk-reducing mastectomy to reduce their breast cancer risk. The analyses were conducted from both payer and societal perspectives. This study was conducted from October 1, 2022, to February 20, 2024. Main Outcomes and Measures: Outcomes of interest were ovarian cancer, breast cancer, additional heart disease deaths, and incremental cost-effectiveness ratio ICER per quality-adjusted life-year (QALY). One-way and probabilistic-sensitivity-analyses (PSA) were undertaken to explore the uncertainty. Results: In the simulated cohort of 1 000 000 women aged 30 years in Canada, the base case ICERs of population-based BRCA testing were CAD $32 276 (US $23 402.84) per QALY from the payer perspective or CAD $16 416 (US $11 903.00) per QALY from the societal perspective compared with FH-based testing, well below the established Canadian cost-effectiveness thresholds. Population testing remained cost-effective for ages 40 to 60 years but not at age 70 years. The results were robust for multiple scenarios, 1-way sensitivity, and PSA. More than 99% of simulations from payer and societal perspectives were cost-effective on PSA (5000 simulations) at the CAD $50 000 (US $36 254.25) per QALY willingness-to-pay threshold. Population-based BRCA testing could potentially prevent an additional 2555 breast cancers and 485 ovarian cancers in the Canadian population, corresponding to averting 196 breast cancer deaths and 163 ovarian cancer deaths per 1 000 000 population. Conclusions and Relevance: In this economic evaluation, population-based BRCA testing was cost-effective compared with FH-based testing in Canada from payer and societal perspectives. These findings suggest that changing the genetic testing paradigm to population-based testing could prevent thousands of breast and ovarian cancers.

Asunto(s)

Neoplasias de la Mama , Análisis Costo-Beneficio , Pruebas Genéticas , Neoplasias Ováricas , Humanos , Femenino , Canadá/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/economía , Neoplasias Ováricas/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/prevención & control , Neoplasias Ováricas/economía , Persona de Mediana Edad , Adulto , Pruebas Genéticas/economía , Pruebas Genéticas/métodos , Años de Vida Ajustados por Calidad de Vida , Proteína BRCA2/genética , Cadenas de Markov , Proteína BRCA1/genética , Detección Precoz del Cáncer/economía , Detección Precoz del Cáncer/métodos , Anciano , Genes BRCA2 , Genes BRCA1

RESUMEN

Cancer, a multifactorial disease characterized by uncontrolled cellular proliferation, remains a global health challenge with significant morbidity and mortality. Genomic and molecular aberrations, coupled with environmental factors, contribute to its heterogeneity and complexity. Chemotherapeutic agents like doxorubicin (Dox) have shown efficacy against various cancers but are hindered by dose-dependent cytotoxicity, particularly on vital organs like the heart and brain. Autophagy, a cellular process involved in self-degradation and recycling, emerges as a promising therapeutic target in cancer therapy and neurodegenerative diseases. Dysregulation of autophagy contributes to cancer progression and drug resistance, while its modulation holds the potential to enhance treatment outcomes and mitigate adverse effects. Additionally, emerging evidence suggests a potential link between autophagy, DNA damage, and caretaker breast cancer genes BRCA1/2, highlighting the interplay between DNA repair mechanisms and cellular homeostasis. This review explores the intricate relationship between cancer, Dox-induced cytotoxicity, autophagy modulation, and the potential implications of autophagy in DNA damage repair pathways, particularly in the context of BRCA1/2 mutations.

Asunto(s)

Autofagia , Daño del ADN , Reparación del ADN , Neoplasias , Humanos , Autofagia/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo , Reparación del ADN/efectos de los fármacos , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Animales , Doxorrubicina/farmacología , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Antineoplásicos/farmacología

RESUMEN

BACKGROUND: Pathogenic BRCA1 or BRCA2 germline mutations contribute to hereditary breast, ovarian, prostate, and pancreatic cancer. Paradoxically, bi-allelic inactivation of BRCA1 or BRCA2 (bBRCA1/2) is embryonically lethal and decreases cellular proliferation. The compensatory mechanisms that facilitate oncogenesis in bBRCA1/2 tumors remain unclear. METHODS: We identified recurrent genetic alterations enriched in human bBRCA1/2 tumors and experimentally validated if these improved proliferation in cellular models. We analyzed mutations and copy number alterations (CNAs) in bBRCA1/2 breast and ovarian cancer from the TCGA and ICGC. We used Fisher's exact test to identify CNAs enriched in bBRCA1/2 tumors compared to control tumors that lacked evidence of homologous recombination deficiency. Genes located in CNA regions enriched in bBRCA1/2 tumors were further screened by gene expression and their effects on proliferation in genome-wide CRISPR/Cas9 screens. A set of candidate genes was functionally validated with in vitro clonogenic survival and functional assays to validate their influence on proliferation in the setting of bBRCA1/2 mutations. RESULTS: We found that bBRCA1/2 tumors harbor recurrent large-scale genomic deletions significantly more frequently than histologically matched controls (n = 238 cytobands in breast and ovarian cancers). Within the deleted regions, we identified 277 BRCA1-related genes and 218 BRCA2-related genes that had reduced expression and increased proliferation in bBRCA1/2 but not in wild-type cells in genome-wide CRISPR screens. In vitro validation of 20 candidate genes with clonogenic proliferation assays validated 9 genes, including RIC8A and ATMIN (ATM-Interacting protein). We identified loss of RIC8A, which occurs frequently in both bBRCA1/2 tumors and is synthetically viable with loss of both BRCA1 and BRCA2. Furthermore, we found that metastatic homologous recombination deficient cancers acquire loss-of-function mutations in RIC8A. Lastly, we identified that RIC8A does not rescue homologous recombination deficiency but may influence mitosis in bBRCA1/2 tumors, potentially leading to increased micronuclei formation. CONCLUSIONS: This study provides a means to solve the tumor suppressor paradox by identifying synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers.

Asunto(s)

Proteína BRCA1 , Proteína BRCA2 , Neoplasias de la Mama , Variaciones en el Número de Copia de ADN , Humanos , Proteína BRCA2/genética , Proteína BRCA1/genética , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proliferación Celular , Línea Celular Tumoral , Mutación , Mutaciones Letales Sintéticas

RESUMEN

Abasic sites are DNA lesions repaired by base excision repair. Cleavage of unrepaired abasic sites in single-stranded DNA (ssDNA) can lead to chromosomal breakage during DNA replication. How rupture of abasic DNA is prevented remains poorly understood. Here, using cryoelectron microscopy (cryo-EM), Xenopus laevis egg extracts, and human cells, we show that RAD51 nucleofilaments specifically recognize and protect abasic sites, which increase RAD51 association rate to DNA. In the absence of BRCA2 or RAD51, abasic sites accumulate as a result of DNA base methylation, oxidation, and deamination, inducing abasic ssDNA gaps that make replicating DNA fibers sensitive to APE1. RAD51 assembled on abasic DNA prevents abasic site cleavage by the MRE11-RAD50 complex, suppressing replication fork breakage triggered by an excess of abasic sites or POLθ polymerase inhibition. Our study highlights the critical role of BRCA2 and RAD51 in safeguarding against unrepaired abasic sites in DNA templates stemming from base alterations, ensuring genomic stability.

Asunto(s)

Proteína BRCA2 , Daño del ADN , Reparación del ADN , Replicación del ADN , ADN de Cadena Simple , Recombinasa Rad51 , Xenopus laevis , Humanos , Recombinasa Rad51/metabolismo , Recombinasa Rad51/genética , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Animales , ADN de Cadena Simple/metabolismo , ADN de Cadena Simple/genética , Microscopía por Crioelectrón , ADN Polimerasa theta , Metilación de ADN , ADN Polimerasa Dirigida por ADN/metabolismo , ADN Polimerasa Dirigida por ADN/genética , Proteína Homóloga de MRE11/metabolismo , Proteína Homóloga de MRE11/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética

RESUMEN

Although overall survival data are still premature, the PROpel study found radiological progression-free survival (PFS) benefits of abiraterone and olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC). However, for patients who have not been genetically tested or lack BRCA1/2 mutations (BRCAm), this combination therapy has been questioned as a first-line conventional treatment for mCRPC, mainly due to significant health economics and side effects. In our retrospective study, we found that treatment with low-dose abiraterone plus olaparib as a late-line treatment for mCRPC could lead to prostate-specific antigen (PSA) and symptom PFS in selective cases even without BRCAm. The median PSA-PFS was 8 months (IQR: 6.5-11.5), with a median follow-up duration of 39.0 months (IQR: 27.5-64.5). Gene tests were conducted in all patients, identifying non-BRCA mutations through ctDNA testing (24%), tumor tissue testing (12%), or both (64%). Adverse events occurred in 72% of patients, with 16% experiencing Grade ≥ 3 events. Common adverse events included anemia (64%), decreased appetite (48%), and fatigue (25%). Our findings support low-dose abiraterone plus olaparib as a potential option for mCRPC patients without BRCAm, offering manageable safety and efficacy profiles.

Asunto(s)

Androstenos , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína BRCA1 , Proteína BRCA2 , Ftalazinas , Piperazinas , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Ftalazinas/administración & dosificación , Ftalazinas/uso terapéutico , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Piperazinas/efectos adversos , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Proteína BRCA2/genética , Androstenos/administración & dosificación , Androstenos/uso terapéutico , Proyectos Piloto , Proteína BRCA1/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Mutación , Antígeno Prostático Específico/sangre , Anciano de 80 o más Años , Supervivencia sin Progresión

RESUMEN

BACKGROUND: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance. METHODS: Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi. RESULTS: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively. CONCLUSIONS: Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.

Asunto(s)

Proteína BRCA1 , Proteína BRCA2 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Animales , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Ratones , Proteína BRCA1/genética , Proteína BRCA2/genética , Femenino , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Piperazinas/farmacología , Piperazinas/uso terapéutico , Indoles/uso terapéutico , Indoles/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Carboplatino/farmacología , Carboplatino/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética

RESUMEN

DSS1, essential for BRCA2-RAD51 dependent homologous recombination (HR), associates with the helical domain (HD) and OB fold 1 (OB1) of the BRCA2 DSS1/DNA-binding domain (DBD) which is frequently targeted by cancer-associated pathogenic variants. Herein, we reveal robust ss/dsDNA binding abilities in HD-OB1 subdomains and find that DSS1 shuts down HD-OB1's DNA binding to enable ssDNA targeting of the BRCA2-RAD51 complex. We show that C-terminal helix mutations of DSS1, including the cancer-associated R57Q mutation, disrupt this DSS1 regulation and permit dsDNA binding of HD-OB1/BRCA2-DBD. Importantly, these DSS1 mutations impair BRCA2/RAD51 ssDNA loading and focus formation and cause decreased HR efficiency, destabilization of stalled forks and R-loop accumulation, and hypersensitize cells to DNA-damaging agents. We propose that DSS1 restrains the intrinsic dsDNA binding of BRCA2-DBD to ensure BRCA2/RAD51 targeting to ssDNA, thereby promoting optimal execution of HR, and potentially replication fork protection and R-loop suppression.

Asunto(s)

Proteína BRCA2 , Replicación del ADN , ADN de Cadena Simple , ADN , Recombinación Homóloga , Mutación , Recombinasa Rad51 , Proteína BRCA2/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/química , Humanos , ADN/metabolismo , Recombinasa Rad51/metabolismo , Recombinasa Rad51/genética , ADN de Cadena Simple/metabolismo , ADN de Cadena Simple/genética , Homeostasis , Unión Proteica , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Dominios Proteicos , Línea Celular Tumoral , Daño del ADN , Complejo de la Endopetidasa Proteasomal

RESUMEN

Homologous recombination deficiency (HRD) score is a reliable indicator of genomic instability. The significance of HRD in nasopharyngeal carcinoma (NPC), particularly its influence on prognosis and the immune microenvironment, has yet to be adequately explored. Understanding HRD status comprehensively can offer valuable insights for guiding precision treatment. We utilised three cohorts to investigate HRD status in NPC: the Zhujiang cohort from local collection and the Hong Kong (SRA288429) and Singapore (SRP035573) cohorts from public datasets. The GATK (genome analysis toolkit) best practice process was employed to investigate germline and somatic BRCA1/2 mutations and various bioinformatics tools and algorithms to examine the association between HRD status and clinical molecular characteristics. We found that individuals with a negative HRD status (no-HRD) exhibited a higher risk of recurrence [hazard ratio (HR), 1.43; 95% confidence interval (CI), 2.03-333.76; p = 0.012] in the Zhujiang cohort, whereas, in the Singapore cohort, they experienced a higher risk of mortality (HR, 26.04; 95% CI, 1.43-34.21; p = 0.016) compared with those in the HRD group. In vitro experiments demonstrated that NPC cells with BRCA1 knockdown exhibit heightened sensitivity to chemoradiotherapy. Furthermore, the HRD group showed significantly higher tumour mutational burden and tumour neoantigen burden levels than the no-HRD group. Immune infiltration analysis indicated that HRD tissues tend to have a non-inflamed tumour microenvironment. In conclusion, patients with HRD exhibit a comparatively favourable prognosis in NPC, possibly associated with a non-inflammatory immune microenvironment. These findings have positive implications for treatment stratification, enabling the selection of more precise and effective therapeutic approaches and aiding in the prediction of treatment response and prognosis to a certain extent.

Asunto(s)

Proteína BRCA1 , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Microambiente Tumoral , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patología , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/inmunología , Masculino , Femenino , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/inmunología , Pronóstico , Persona de Mediana Edad , Proteína BRCA1/genética , Proteína BRCA2/genética , Mutación , Adulto , Recombinación Homóloga/genética , Biomarcadores de Tumor/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/genética , Inestabilidad Genómica

RESUMEN

BACKGROUND: Germline breast cancer susceptibility gene (gBRCA) mutation in patients with pancreatic cancer (PC) is not common in clinical practice. Therefore, factors that efficiently show gBRCA mutations and the real-world outcomes of olaparib maintenance therapy have not been fully established. In the present study, we clarified the indicators for the effective detection of gBRCA mutation and the efficacy and safety of olaparib as maintenance therapy. METHODS: We retrospectively analyzed 84 patients with PC who underwent gBRCA testing (BRACAnalysis, Myriad Genetics, Salt Lake City, UT, USA) at our institute between January 2021 and March 2022. For each patient, clinical data were extracted from medical records. RESULTS: The median patient age was 64 y (29-85 y), and 41 patients (48.8%) were male. The gBRCA mutations were identified in 10 (11.9%) patients; two patients had BRCA1 mutation and eight had BRCA2 mutation. All patients with gBRCA mutation had a family history of any cancer, and eight of them had a family history of Hereditary Breast and Ovarian Cancer syndrome (HBOC)-related cancer. The gBRCA mutation rate was higher for patients with PC with a family history of HBOC-related cancer compared to that in patients with PC having a family history of other cancers and no family history of cancer (22.9% vs. 4.1%; P = 0.014). In our study, eight out of 10 patients with gBRCA-positive PC received olaparib after platinum-based chemotherapy. The best responses to platinum-based chemotherapy included a complete response in one patient (12.5%) and a partial response in seven patients (87.5%). The median duration of treatment with platinum-based chemotherapy plus olaparib was 17.5 months (8-87 months), and the duration of treatment with olaparib maintenance therapy was 11 months (1-30 months). During olaparib maintenance therapy, three patients showed no disease progression. One of these three patients underwent conversion surgery after receiving olaparib for 12 months. CONCLUSIONS: The gBRCA testing should be considered proactively, especially in patients with PC with a family history of HBOC-related cancer.

Asunto(s)

Proteína BRCA1 , Proteína BRCA2 , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias Pancreáticas , Ftalazinas , Piperazinas , Humanos , Ftalazinas/uso terapéutico , Persona de Mediana Edad , Femenino , Anciano , Masculino , Adulto , Estudios Retrospectivos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Anciano de 80 o más Años , Piperazinas/uso terapéutico , Piperazinas/administración & dosificación , Proteína BRCA2/genética , Proteína BRCA1/genética , Quimioterapia de Mantención , Pruebas Genéticas/métodos , Relevancia Clínica

RESUMEN

BACKGROUND: In this article, we delineate a loosely selected cohort comprising patients with a history of early-onset breast cancer and/or a familial occurrence of cancer. The aim of this study was to gain insights into the presence of breast cancer-related gene variants in a population from a micro-region in southern Brazil, specifically the Metropolitan Region of Curitiba. This area exhibits a highly genetically mixed population, mirroring the general characteristics of the Brazilian people. METHODS: Comprehensive next-generation sequencing (NGS) multigene panel testing was conducted on 12 patients from the region, utilizing three different library preparation methods. RESULTS: Two pathogenic variants and one candidate pathogenic variant were identified: BRCA2 c.8878C>T, p.Gln2960Ter; CHEK2 c.1100del, p.Thr367Metfs15, and BRCA2 c.3482dup, p.Asp1161Glufs3. CONCLUSION: BRCA2 c.3482dup, a novel candidate pathogenic variant, previously unpublished, is reported. The prevalence of pathogenic variants in this small cohort is similar to that described in the literature. All different library preparation methods were equally proficient in enabling the detection of these variants.

Asunto(s)

Proteína BRCA2 , Neoplasias de la Mama , Quinasa de Punto de Control 2 , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteína BRCA2/genética , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quinasa de Punto de Control 2/genética , Brasil , Persona de Mediana Edad , Adulto , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Predisposición Genética a la Enfermedad

RESUMEN

Ovarian carcinoma remains the most lethal gynaecologic malignancy. Half of all high-grade serous ovarian cancers (HGSOCs) have a homologous recombination deficiency (HRD) with regard to the repair of double-strand DNA breaks and are candidate to receive maintenance treatment with PARP inhibitors. While a wealth of literature exists regarding the therapeutic guidance of patients from a medical standpoint, the influence of the HRD status on the surgical outlook has been comparatively limited. In this review, the clinical and biological features of advanced ovarian cancers with BRCA1/2 mutation and/or HRD status are considered with particular reference to their impact on the surgical management and on the medico-surgical sequence. The modification of the surgical indications according to the results of molecular testing in first-line and recurrent settings are discussed.

Asunto(s)

Carcinoma Epitelial de Ovario , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/cirugía , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/diagnóstico , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Ováricas/diagnóstico , Proteína BRCA1/genética , Mutación , Proteína BRCA2/genética , Manejo de la Enfermedad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico

RESUMEN

PURPOSE: This study seeks to contribute real-world data on the prevalence of BRCA1/2 and HRR gene mutations in prostate cancer. METHODS: We compiled sequencing data of 197 cases of primary and metastatic prostate cancer, in which HRR mutation analysis was performed upon clinical request within the last 5 years. All cases were analyzed using a targeted NGS BRCAness multigene panel, including 8 HRR genes (ATM, BRCA1, BRCA2, CDK12, CHEK2, FANCA, HDAC2, PALB2). RESULTS: Our findings reveal a prevalence of potentially targetable mutations based on FDA criteria of 20.8%, which is comparable to the literature. However, the frequency of targetable BRCA2 mutations within our cohort was lower than reported for mCRPC and ATM and CHEK2 mutations were more prevalent instead. Thus, while 20.8% (n = 38) of the cases meet the criteria for olaparib treatment per FDA approval, only 4.9% (n = 9) align with the eligibility criteria according to the EMA approval. CONCLUSION: This study offers valuable real-world insights into the landscape of BRCA1/2 and HRR gene mutations and the practical clinical management of HRR gene testing in prostate cancer, contributing to a better understanding of patient eligibility for PARPi treatment.

Asunto(s)

Proteína BRCA1 , Proteína BRCA2 , Neoplasias de la Próstata Resistentes a la Castración , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Proteína BRCA1/genética , Proteína BRCA2/genética , Genes BRCA1 , Genes BRCA2 , Mutación , Metástasis de la Neoplasia , Prevalencia , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología

RESUMEN

Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.

Asunto(s)

Glucólisis , Carcinoma de Células Escamosas de Cabeza y Cuello , Animales , Humanos , Ratones , Glucólisis/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/deficiencia , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Proteína BRCA2/deficiencia , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Regulación Neoplásica de la Expresión Génica , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Femenino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Regiones Promotoras Genéticas/genética , Proteína de la Leucemia Mieloide-Linfoide