Cancer Trends in Inborn Errors of Immunity: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with inborn errors of immunity (IEI) are susceptible to developing cancer due to defects in the immune system. The prevalence of cancer is higher in IEI patients compared to the immunocompetent population and cancers are considered as an important and common cause of death in IEI patients. OBJECTIVES: To systematically review demographic, genetic and cancer-related data of IEI patients with a history of malignancy. Moreover, we performed a meta-analysis aiming to determine the frequency of cancer in patients with different types of IEI. METHODS: We conducted electronic searches on Embase, Web of Science, PubMed, and Scopus (until September 2023) introducing terms related to IEI and cancer. Studies with human subjects with confirmed IEI who had developed at least one malignancy during their lifetime were included. RESULTS: A total number of 4607 IEI patients with a cancer history were included in the present study. Common variable immunodeficiency (CVID) had the highest number of reported cases (1284 cases), mainly due to a higher relative proportion of patients with predominantly antibody deficiencies (PAD) and their increased life expectancy contributing to the higher detection and reporting of cancers among these patients. The most common malignancy was hematologic/blood cancers (3026 cases, mainly diffuse large B cell lymphoma). A total number of 1173 cases (55.6%) succumbed to cancer, with the highest rate of bone marrow failure (64.9%). Among the patients with monogenic defects in IEI-associated genes, the majority of cases had ATM deficiency (926 cases), but the highest cancer frequency rate belonged to NBS1 deficiency (50.5%). 1928 cases out of total 4607 eligible cases had detailed data to allow further statistical analysis that revealed BRCA2 deficiency had the earliest cancer development (~ 38 months), lowest cure frequency, and highest fatality rate (85%), while ATM deficiency had the lowest cure frequency and highest fatality rate (72%) among total cases reviewed with exclusion of Fanconi anemia. CONCLUSION: The overall reported cancer frequency in the cases reviewed with and without exclusion of Fanconi anemia was 11.1% (95% confidence interval: 9.8-12.5%) and 12.0% (95% confidence interval: 10.6-13.5%), respectively. Our study revealed that the incidence of cancer is significantly dependent on the molecular and pathway defects in IEI patients, and individualized early screening and appropriate treatment, might improve the prognosis of these patients.

New Prognostic Biomarkers in Metastatic Castration-Resistant Prostate Cancer.

Prostate cancer is one of the most frequent cancers in men and is a common cause of cancer-related death. Despite significant progress in the diagnosis and treatment of this tumor, patients who relapse after radical treatments inevitably develop metastatic disease. Patient stratification is therefore key in this type of cancer, and there is an urgent need for prognostic biomarkers that can define patients' risk of cancer-related death. In the last 10 years, multiple prognostic factors have been identified and studied. Here, we review the literature available and discuss the most common aberrant genomic pathways in metastatic castration-resistant prostate cancer shown to have a prognostic relevance in this setting.

New Mechanisms of DNA Repair Defects in Fused in Sarcoma-Associated Neurodegeneration: Stage Set for DNA Repair-Based Therapeutics?

Genome damage and defective DNA repair are etiologically linked to several neurodegenerative disorders, including fused in sarcoma (FUS)-associated amyotrophic lateral sclerosis (ALS). However, the underlying mechanisms remain enigmatic, which is a roadblock for exploiting genome repair-targeted therapies. Our recent studies identified defects in DNA nick ligation and oxidative damage repair caused by mutations in the RNA/DNA-binding protein FUS in familial ALS patients. In healthy neurons, FUS protects the genome by facilitating PARP1-dependent recruitment of XRCC1/DNA Ligase IIIα (LigIII) to oxidized genome sites and activating LigIII via direct interaction. This is a critical step in the repair of oxidative genome damage, a foremost challenge for postmitotic neurons due to their high oxygen consumption. We discovered that mutant FUS significantly inhibited the recruitment of XRCC1/LigIII to DNA strand breaks, causing defects in DNA ligation during the repair of oxidative DNA damage, which contributed to neurodegeneration. While the FUS loss of function was responsible for the repair defects, increased oxidative genome damage due to mutant FUS aggregation could exacerbate the phenomenon. We highlight how these new molecular insights into previously undescribed DNA repair defect linked to FUS-associated neurodegeneration could provide an important opportunity for exploring DNA repair-based therapeutic avenues.

Immune System and DNA Repair Defects in Ovarian Cancer: Implications for Locoregional Approaches.

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

Beyond DNA repair: the novel immunological potential of PARP inhibitors.

Loss of excision repair cross-complementation group 1 (ERCC1), frequently found in lung cancer, and mutations in breast cancer type 1/2 susceptibility genes (BRCA1/2), often found in ovarian, breast and prostate cancers, confer sensitivity to poly-(ADP-ribose) polymerase inhibitors (PARPi). Our work, and that of others, shows that PARPi selectively trigger tumor cell-autonomous immune phenotypes in ERCC1- or BRCA-defective contexts. This suggests that PARPi, used in appropriately selected populations, might mediate their therapeutic effects by potentiating anti-tumor immunity.

Genetic analysis of undiagnosed ataxia-telangiectasia-like disorders.

OBJECTIVES: Defects in DNA damage responses or repair mechanisms cause numerous rare inherited diseases, referred to as "DNA-repair defects" or "DNA damage deficiency", characterized by neurodegeneration, immunodeficiency, and/or cancer predisposition. Early accurate diagnosis is important for informing appropriate clinical management; however, diagnosis is frequently challenging and can be delayed, due to phenotypic heterogeneity. Comprehensive genomic analysis could overcome this disadvantage. The objectives of this study were to determine the prevalence of ataxia-telangiectasia (A-T) and A-T-like DNA-repair defects in Japan and to determine the utility of comprehensive genetic testing of presumptively diagnosed patients in facilitating early diagnosis. METHODS: A nationwide survey of diseases presumably caused by DNA-repair defects, including A-T, was performed. Additionally, comprehensive next-generation sequencing (NGS) analysis, targeting known disease-causing genes, was conducted. RESULTS: Sixty-three patients with A-T or other diseases with characteristics of DNA-repair defects were identified. Thirty-four patients were genetically or clinically definitively diagnosed with A-T (n = 22) or other DNA-repair defects (n = 12). Genetic analysis of 17 presumptively diagnosed patients revealed one case of ataxia with oculomotor apraxia type 1 (AOA1); one ataxia with oculomotor apraxia type 2 (AOA2); two types of autosomal dominant spinocerebellar ataxia (SCA5, SCA29); two CACNA1A-related ataxias; one microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR); and one autosomal dominant KIF1A-related disorder with intellectual deficit, cerebellar atrophy, spastic paraparesis, and optic nerve atrophy. The diagnostic yield was 58.8%. CONCLUSION: Comprehensive genetic analysis of targeted known disease-causing genes by NGS is a powerful diagnostic tool for subjects with indistinguishable neurological phenotypes resembling DNA-repair defects.

The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management.

Hyper Immunoglobulin M syndrome (HIGM) is a rare primary immunodeficiency disorder characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM. Various X-linked and autosomal recessive/dominant mutations have been reported as the underlying cause of the disease. Based on the underlying genetic defect, the affected patients present a variety of clinical manifestations including pulmonary and gastrointestinal complications, autoimmune disorders, hematologic abnormalities, lymphoproliferation and malignancies which could be controlled by multiple relevant therapeutic approaches. Herein, the epidemiology, pathogenesis, clinical manifestations, diagnosis, management, prognosis and treatment in patients with HIGM syndrome have been reviewed.

Utility of DNA, RNA, Protein, and Functional Approaches to Solve Cryptic Immunodeficiencies.

PURPOSE: We report a female infant identified by newborn screening for severe combined immunodeficiencies (NBS SCID) with T cell lymphopenia (TCL). The patient had persistently elevated alpha-fetoprotein (AFP) with IgA deficiency, and elevated IgM. Gene sequencing for a SCID panel was uninformative. We sought to determine the cause of the immunodeficiency in this infant. METHODS: We performed whole-exome sequencing (WES) on the patient and parents to identify a genetic diagnosis. Based on the WES result, we developed a novel flow cytometric panel for rapid assessment of DNA repair defects using blood samples. We also performed whole transcriptome sequencing (WTS) on fibroblast RNA from the patient and father for abnormal transcript analysis. RESULTS: WES revealed a pathogenic paternally inherited indel in ATM. We used the flow panel to assess several proteins in the DNA repair pathway in lymphocyte subsets. The patient had absent phosphorylation of ATM, resulting in absent or aberrant phosphorylation of downstream proteins, including γH2AX. However, ataxia-telangiectasia (AT) is an autosomal recessive condition, and the abnormal functional data did not correspond with a single ATM variant. WTS revealed in-frame reciprocal fusion transcripts involving ATM and SLC35F2 indicating a chromosome 11 inversion within 11q22.3, of maternal origin. Inversion breakpoints were identified within ATM intron 16 and SLC35F2 intron 7. CONCLUSIONS: We identified a novel ATM-breaking chromosome 11 inversion in trans with a pathogenic indel (compound heterozygote) resulting in non-functional ATM protein, consistent with a diagnosis of AT. Utilization of several molecular and functional assays allowed successful resolution of this case.

Emerging Therapies in Metastatic Prostate Cancer.

PURPOSE OF REVIEW: In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. RECENT FINDINGS: Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature.

DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies.

As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single-strand or double-strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or, after a latency period, cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. Although the application of PARP inhibitors (PARPis) initially focused on tumors with BRCA1 or BRCA2 deficiencies, synthetic susceptibilities to PARPis have been expanded due to the identification of tumors with mutations pathways involved in DNA damage repair, in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder cancer and especially prostate cancer, contain subsets of patients with germline and somatic alterations in HR genes that may reflect an increased response to PARPis. In this review, the authors describe the mechanisms and rationale of the use of PARPis in patients with GU cancers, summarize previously reported preclinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can have widespread application in patients with GU cancers. Cancer 2017;123:1912-1924. © 2017 American Cancer Society.

Inherited DNA repair gene mutations detected by tumor next generation sequencing in urinary tract cancers.

Interpretation of next-generation sequencing (NGS) of tumor tissue in patients with advanced Urinary Tract Cancer (UTC) is performed to guide treatment selection but may reveal pathogenic variants with germline implications. We identified three patients with UTC with unexpected germline DNA repair gene mutations. Specific testing for these was prompted by the detection of these mutations by tumor NGS. All three patients were nonsmokers with a strong family history of cancer. Two patients had upper tract UTC with age at diagnosis in the 40 s. One had a family history suggestive of hereditary breast/ovarian predisposition and a FANCA mutation detected on NGS was confirmed to be germline. The second patient had a family history suggestive of Lynch syndrome but was found to have a germline BRCA2 mutation that was suggested by NGS. The third patient had bladder cancer at an advanced age, a family history of late-onset gastrointestinal malignancies that did not meet criteria for clinical testing for a hereditary cancer predisposition syndrome. NGS identified an MUTYH mutation, and targeted testing confirmed a monoallelic germline MUTYH mutation. Detection of variants with germline implications by tumor NGS may be clinically relevant for patients and their families and warrant genetic counseling and germline genetic testing. The prevalence of germline DNA repair defects in the context of inherited predisposition to UTC merits further study.

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated aging and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases.

Fatal Lymphoproliferative Disease in Two Siblings Lacking Functional FAAP24.

Hereditary defects in several genes have been shown to disturb the normal immune response to EBV and to give rise to severe EBV-induced lymphoproliferation in the recent years. Nevertheless, in many patients, the molecular basis of fatal EBV infection still remains unclear. The Fanconi anemia-associated protein 24 (FAAP24) plays a dual role in DNA repair. By association with FANCM as component of the FA core complex, it recruits the FA core complex to damaged DNA. Additionally, FAAP24 has been shown to evoke ATR-mediated checkpoint responses independently of the FA core complex. By whole exome sequencing, we identified a homozygous missense mutation in the FAAP24 gene (cC635T, pT212M) in two siblings of a consanguineous Turkish family who died from an EBV-associated lymphoproliferative disease after infection with a variant EBV strain, expressing a previously unknown EBNA2 allele.In order to analyze the functionality of the variant FAAP24 allele, we used herpes virus saimiri-transformed patient T cells to test endogenous cellular FAAP24 functions that are known to be important in DNA damage control. We saw an impaired FANCD2 monoubiquitination as well as delayed checkpoint responses, especially affecting CHK1 phosphorylation in patient samples in comparison to healthy controls. The phenotype of this FAAP24 mutation might have been further accelerated by an EBV strain that harbors an EBNA2 allele with enhanced activities compared to the prototype laboratory strain B95.8. This is the first report of an FAAP24 loss of function mutation found in human patients with EBV-associated lymphoproliferation.