High Risk Of Developing Cancer Research Articles

Clonal landscape and clinical outcomes of telomere biology disorders: somatic rescue and cancer mutations

AbstractTelomere biology disorders (TBDs), caused by pathogenic germ line variants in telomere-related genes, present with multiorgan disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBDs is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 patients with TBD with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, and splicing factor genes were associated with poorer overall survival. Chr1q+ and splicing factor or TP53 mutations significantly increased the risk of hematologic malignancies, regardless of clonal burden. Chr1q+ and U2AF1S34 mutated clones were premalignant events associated with the secondary acquisition of mutations in genes related to hematologic malignancies. Similar to the known effects of Chr1q+ and TP53-CH, functional studies demonstrated that U2AF1S34 mutations primarily compensated for aberrant upregulation of TP53 and interferon pathways in telomere-dysfunctional hematopoietic stem cells, highlighting the TP53 pathway as a canonical route of malignancy in TBD. In contrast, somatic POT1/PPM1D/TERTp mutations had distinct trajectories unrelated to cancer development. With implications beyond TBD, our data show that telomere dysfunction is a strong selective pressure for CH. In TBD, CH is a poor prognostic marker associated with worse overall survival. The identification of key regulatory pathways that drive clonal transformation in TBD allows for the identification of patients at a higher risk of cancer development.

Cancer incidence and mortality in the Far Eastern Federal District (2013–2022)

The aim of the study was to assess the territorial patterns in cancer incidence and mortality among the population of the Far Eastern Federal District in the period 2013–2022. Material and Methods. Data from official reports of cancer services (form No 35, No. 7) processed using standard cancer statistics programs were presented. Results. In the east of the country, 31,822 new cancer cases were registered in 2022, which was 1.3 % more than in 2021. The average cancer incidence rate in males was 294.06 ± 5.05 per 100,000 (2020: 296.94 ± 4.66), with a decrease rate of 3.0 %. In females, the equivalent rate increased to 240.96 ± 5.73 per 100,000 (2020: 237.92 ± 6.26 per 100,000) with a rise of 6.3 %. Skin cancer was the most common malignancy (11.6 %) followed by trachea, bronchi, lung (11.5 %), breast (11.3 %) and colon (6.3 %) cancers. The percent of actively detected patients increased to 23.2 % (2013: 14.0 %) as did the index of accumulation of contingents – 7.3 (2013: 5.3). The number of patients with stage I–II cancer increased to 57.0 % (2013: 47.5 %), while the number of stage III-IV cancers decreased to 20.8 % (2013: 24.7 %). The number of morphologic studies (94.1 %) was lower than the average for RF (95.8 %). The proportion of patients registered for five or more years decreased to 57.2 % (RF: 58.2 %). The average cancer mortality rate in men was 174.99 ± 3.10 per 100,000 (2020: 181.76 ± 2.51 per 100,000). The average cancer mortality rate in women was lower than in men, being 91.34 ± 1.20 per 100,000 (2020: 93.71 ± 0.80о per 100,000). Cancers of trachea, bronchi and lung (20.0 %), stomach (8.9 %), colon (7.0 %) and breast (6.6 %) were the leading causes of mortality. Conclusion. The low level of active cancer detection did not significantly change the incidence rates during the study period. A greater volume of preventive measures with improvement of their quality will enable the primary health care system to detect cancer at early stages, form groups being at high risk for cancer development and, consequently, to reduce mortality rates. A prerequisite for improving medical care for cancer patients is the continuous training of professional staff and the use of modern diagnostic and treatment technologies.

Paraneoplastic Syndrome After Kidney Transplantation: Frequency, Risk Factors, Differences to Paraneoplastic Occurrence of Glomerulonephritis in the Native Kidney, and Implications on Long-Term Kidney Graft Function.

Posttransplant malignancies are an important complication of solid organ transplantation. Kidney transplant recipients are at particularly high risk of cancer development. The most relevant risk factors of carcinogenesis are the use of immunosuppressive agents and oncogenic viral infections. Additionally, immune dysregulation caused by these factors may predispose to various types of organ damage. Paraneoplastic glomerular diseases are one of the most interesting and understudied cancer manifestations. The appropriate diagnosis of paraneoplastic glomerular damage can be challenging in kidney transplant recipients, due to factors inherent to concomitant medication and common comorbidities. Recent advances in the field of molecular and clinical nephrology led to a significant improvement in our understanding of glomerular diseases and their more targeted treatment. On the other hand, introduction of novel anticancer drugs tremendously increased patients' survival, at the cost of kidney-related side effects. Our review aims to provide insights into diagnosis and treatment of paraneoplastic glomerular diseases, with a special attention to kidney transplant recipients.

The PIG-A gene mutation assay in human biomonitoring and disease.

The blood cell phosphatidylinositol glycan class A (PIG-A) gene mutation assay has been extensively researched in rodents for in vivo mutagenicity testing and is now being investigated in humans. The PIG-A gene is involved in glycosyl phosphatidylinositol (GPI)-anchor biosynthesis. A single mutation in this X-linked gene can lead to loss of membrane-bound GPI anchors, which can be enumerated via corresponding GPI-anchored proteins (e.g., CD55) using flow cytometry. The studies published to date by different research groups demonstrate a remarkable consistency in PIG-A mutant frequencies. Moreover, with the low background level of mutant erythrocytes in healthy subjects (2.9-5.56 × 10-6 mutants), induction of mutation post genotoxic exposure can be detected. Cigarette smoking, radiotherapy, and occupational exposures, including lead, have been shown to increase mutant levels. Future applications of this test include identifying new harmful agents and establishing new exposure limits. This mutational monitoring approach may also identify individuals at higher risk of cancer development. In addition, identifying protective agents that could mitigate these effects may reduce baseline somatic mutation levels and such behaviors can be encouraged. Further technological progress is required including establishing underlying mechanisms of GPI anchor loss, protocol standardization, and the development of cryopreservation methods to improve GPI-anchor stability over time. If successful, this assay has the potential be widely employed, for example, in rural and low-income countries. Here, we review the current literature on PIG-A mutation in humans and discuss the potential role of this assay in human biomonitoring and disease detection.

Cancer screening and management in the transgender population: Review of literature and special considerations for gender affirmation surgery.

Literature focused on cancer screening and management is lacking in the transgender population. To action to increase contributions to the scientific literature that drives the creation of cancer screening and management protocols for transgender and gender nonconforming (TGNC) patients. We performed a systematic search of PubMed on January 5th, 2022, with the following terms: "TGNC", OR "transgender", OR "gender non-conforming", OR "gender nonbinary" AND "cancer screening", AND "breast cancer", AND "cervical cancer", AND "uterine cancer", AND "ovarian cancer", AND "prostate cancer", AND "testicular cancer", AND "surveillance", AND "follow-up", AND "management". 70 unique publications were used. The findings are discussed under "Screening" and "Management" categories. Screening: Current cancer screening recommendations default to cis-gender protocols. However, long-term gender-affirming hormone therapy and loss to follow-up from the gender-specific specialties contribute to a higher risk for cancer development and possible delayed detection. The only known screening guidelines made specifically for this population are from the American College of Radiology for breast cancer. Management: Prior to undergoing Gender Affirmation Surgery (GAS), discussion should address cancer screening and management in the organs remaining in situ. Cancer treatment in this population requires consideration for chemotherapy, radiation, surgery and/or reconstruction. Modification of hormone therapy is decided on a case-by-case basis. The use of prophylactic vs aesthetic techniques in surgery is still debated. When assessing transgender individuals for GAS, a discussion on the future oncologic risk of the sex-specific organs remaining in situ is essential. Cancer management in this population requires a multidisciplinary approach while the care should be highly individualized with considerations to social, medical, surgical and gender affirming surgery related specifications. Special considerations have to be made during planning for GAS as surgery will alter the anatomy and may render the organ difficult to sample for screening purposes. A discussion with the patient regarding the oncologic risk of remaining organs is imperative prior to GAS. Other special considerations to screening such as the conscious or unconscious will to unassociated with their remaining organs is also a key point to address. We currently lack high quality studies pertinent to the cancer topic in the gender affirmation literature. Further research is required to ensure more comprehensive and individualized care for this population.

Brief status of contamination in surface water of rivers of India by heavy metals: a review with pollution indices and health risk assessment.

Water is polluted via various means; among these, heavy metal (HM) contamination is of great concern because of the involvement of metal toxicity and its effect on aquatic environment. The significance and novelty of this study is that it focuses on assessment of HMs in the surface water of Indian rivers only from 1991 to 2021. For this, multivariate studies were used to find multiple sources of HMs. The average concentrations of Fe, Cr, Pb, Ni, Cd, Mn, Hg, Co, and As in surface water of rivers were found to far exceed the permitted limits established by both World Health Organisation and Bureau of Indian Standards. The HM indices like HM pollution, degree of contamination, evaluation index, water pollution, and toxicity load data all indicated that the rivers under investigation are heavily polluted by HMs. In this study, health risk assessment indicated non-carcinogenic effects of Fe, Cr, Cu, Pb, Cd, Mn, Hg, Co, and As in children and those of Fe, Cr, Pb, Cd, Hg, Co, and As in adults. Values investigated for Cancer index were higher for Cr, Pb, Ni, Cd, and As indicating a high risk of cancer development in adults and children via the ingestion pathway than the cutaneous pathway. Moreover, children are more prone to be exposed to both non-carcinogenic and carcinogenic effects of HMs than adults. To reduce human dangers, remediation approaches, such as environment-friendly, cost-effective adsorbents, phytoremediation and bio-remediation, as well as tools like bio-sensors, should be included in river management plans.

THE ROLE OF NUTRITIONAL RESTRICTION IN THE PATHOGENESIS OF MALIGNANT TUMORS

Cancer is one of the leading causes of death in developed countries. Cancer incidence is growing, and it may be associated with longer life expectancy that leads to higher risk of cancer development. Metabolic changes are among the most important aspects of the tumor progression, which appear both in the tumor cells themselves and in the tumor microenvironment, affecting later the entire organism as a whole. Abnormal metabolism of tumor cells, including activation of aerobic glycolysis and enhancement of anabolic pathways, is important in metastasizing, medical drug resistance, and in the implementation of tumor stem cell viability programs.

PECULIARITIES OF INFLUENCE MADE BY DIABETES MELLITUS AS COMORBID PATHOLOGY ON THE SYSTEM OF SEX HORMONES AND THEIR RECEPTORS IN TUMORS OF DIFFERENT HISTOLOGICAL ORIGIN

Improving the survival of cancer patients contributes to a growing number of patients with chronic comorbidities, including diabetes mellitus (DM). Moreover, higher risk of cancer development in patients with DM and poor prognosis determine the importance of studying the mechanisms mediating the effect of altered glucose metabolism made on the growth and metastasis of malignant tumors [3,4]. The polyetiology of both pathologies and the presence of research studies that do not confirm a direct relationship between DM and the development of malignant neoplasms indicate the complex nature of their relationship with the possible context-dependent regulation of many cellular processes associated with carcinogenesis and the development of DM [1,2]. An important role in the processes of the regulation is played by an imbalance in the system of sex hormones.

FANCONI ANEMIA - ORAL REPERCUSSIONS AND DENTAL MANAGEMENT

<h3>Objectives</h3> Fanconi anemia (FA) is a rare genetic disease characterized by bone marrow failure and increased predisposition for cancer development, mainly oral squamous cell carcinoma (OSCC). The aim of this study was to discuss oral repercussions and dental management in patients with FA, focusing on the relevance of the dental surgeon (DS) in the OSCC prevention. <h3>Study Design</h3> A literature research was conducted in the PubMed, Scielo, and Google Scholar databases using the descriptors: Fanconi anemia, squamous cell carcinoma, oral manifestations, dental management, and dentistry. <h3>Results</h3> Besides the high risk of cancer development, patients with FA could also present aplastic anemia, pancytopenia, short stature, and kidney and heart defects. The only effective treatment to the bone marrow failure is allogeneic hematopoietic stem cell transplantation; however, this does not prevent OSCC occurrence. Therefore, the DS is important to prevent potential infections and to diagnose OSCC in its early stages, allowing to these patients a better opportunity for cure. <h3>Conclusions</h3> Dental follow-up of patients with FA should be mandatory because DS plays an essential role not only in the management of oral manifestations but also in the early detection of the OSCC that sometimes could be presented as the first FA symptom.

Dysplastic Stem Cell Plasticity Functions as a Driving Force for Neoplastic Transformation of Precancerous Gastric Mucosa

Dysplasia carries a high risk of cancer development; however, the cellular mechanisms for dysplasia evolution to cancer are obscure. We have previously identified 2 putative dysplastic stem cell (DSC) populations, CD44v6neg/CD133+/CD166+ (double positive [DP]) and CD44v6+/CD133+/CD166+ (triple positive [TP]), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of noncancerous Trop2+/CD133+/CD166+ DSCs initially developed in the transition from precancerous metaplasia to dysplasia in the stomach. Dysplastic organoids established from active Kras-induced mouse stomachs were used for transcriptome analysis, invitro differentiation, and invivo tumorigenicity assessments of DSCs. Cell heterogeneity and genetic alterations during clonal evolution of DSCs were examined by next-generation sequencing. Tissue microarrays were used to identify DSCs in human dysplasia. We additionally evaluated the effect of casein kinase 1 alpha (CK1α) regulation on the DSC activities using both mouse and human dysplastic organoids. We identified a high similarity of molecular profiles between DP- and TP-DSCs, but more dynamic activities of DP-DSCs in differentiation and survival for maintaining dysplastic cell lineages through Wnt ligand-independent CK1α/β-catenin signaling. Xenograft studies demonstrated that the DP-DSCs clonally evolve toward multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Last, growth and survival of both mouse and human dysplastic organoids were controlled by targeting CK1α. These findings indicate that the DSCs are de novo gastric cancer-initiating cells responsible for neoplastic transformation and a promising target for intervention in early induction of gastric cancer.

Brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury

Cancer cells frequently co-opt molecular programs that are normally activated in specific contexts, such as embryonic development and the response to injury. Determining the impact of cancer-associated mutations on cellular phenotypes within these discrete contexts can provide new insight into how such mutations lead to dysregulated cell behaviors and subsequent cancer onset. Here we assess the impact of heritable BRCA2 mutation on embryonic development and the injury response using a zebrafish model (Danio rerio). Unlike most mouse models for BRCA2 mutation, brca2-mutant zebrafish are fully viable and thus provide a unique tool for assessing both embryonic and adult phenotypes. We find that maternally provided brca2 is critical for normal oocyte development and embryonic survival in zebrafish, suggesting that embryonic lethality associated with BRCA2 mutation is likely to reflect defects in both meiotic and embryonic developmental programs. On the other hand, we find that adult brca2-mutant zebrafish exhibit aberrant proliferation of several cell types under basal conditions and in response to injury in tissues at high risk for cancer development. These divergent effects exemplify the often-paradoxical outcomes that occur in embryos (embryonic lethality) versus adult animals (cancer predisposition) with mutations in cancer susceptibility genes such as BRCA2. The altered cell behaviors identified in brca2-mutant embryonic and adult tissues, particularly in adult tissues at high risk for cancer, indicate that the effects of BRCA2 mutation on cellular phenotypes are both context- and tissue-dependent.

High-Grade Cervical Intraepithelial Neoplasia (CIN) Associates with Increased Proliferation and Attenuated Immune Signaling.

Implementation of high-risk human papilloma virus (HPV) screening and the increasing proportion of HPV vaccinated women in the screening program will reduce the percentage of HPV positive women with oncogenic potential. In search of more specific markers to identify women with high risk of cancer development, we used RNA sequencing to compare the transcriptomic immune-profile of 13 lesions with cervical intraepithelial neoplasia grade 3 (CIN3) or adenocarcinoma in situ (AIS) and 14 normal biopsies from women with detected HPV infections. In CIN3/AIS lesions as compared to normal tissue, 27 differential expressed genes were identified. Transcriptomic analysis revealed significantly higher expression of a number of genes related to proliferation, (CDKN2A, MELK, CDK1, MKI67, CCNB2, BUB1, FOXM1, CDKN3), but significantly lower expression of genes related to a favorable immune response (NCAM1, ARG1, CD160, IL18, CX3CL1). Compared to the RNA sequencing results, good correlation was achieved with relative quantitative PCR analysis for NCAM1 and CDKN2A. Quantification of NCAM1 positive cells with immunohistochemistry showed epithelial reduction of NCAM1 in CIN3/AIS lesions. In conclusion, NCAM1 and CDKN2A are two promising candidates to distinguish whether women are at high risk of developing cervical cancer and in need of frequent follow-up.

Role of IL-1β rs1143634 (+3954C>T) polymorphism in cancer risk: an updated meta-analysis and trial sequential analysis.

ObjectiveOxidative stress caused by the pro-inflammatory cytokine interleukin (IL)-1β has been widely investigated for cancer risk. In this study, we focused on the role of IL-1β rs1143634 polymorphism to reveal its impact on cancer development.MethodsRelated studies with fixed inclusion criteria were selected from electronic databases to May 2021. This meta-analysis was performed with odds ratios and 95% confidence intervals. Heterogeneity, publication bias and sensitivity analyses were also conducted. Trial sequential analysis (TSA) and in-silico gene expression analysis were performed.ResultsForty-four case–control studies involving 18,645 patients with cancer and 22,882 controls were included. We observed a significant association of this single nucleotide polymorphism with overall cancer risk in the codominant model 3 (1.13-fold), recessive model (1.14-fold) and allelic model (1.08-fold). Subgroup analysis revealed that rs1143634 elevated the risk of gastric cancer, breast cancer and multiple myeloma. In addition, Asian and mixed populations and hospital-based controls had a significantly higher risk of cancer development. TSA confirmed our findings.ConclusionOur meta-analysis revealed that the presence of IL-1β rs1143634 polymorphism increases the risk of cancer development. Among polymorphism carriers, the Asian population has a higher risk than other ethnic populations.This meta-analysis was registered retrospectively at INPLASY (https://inplasy.com/, INPLASY2021100044).

Influence of Metabolic Syndrome on Cancer Risk in HBV Carriers: A Nationwide Population Based Study Using the National Health Insurance Service Database.

Purpose: Hepatitis B virus (HBV) infection and metabolic syndrome (MS) are known independent risk factors for hepatocellular carcinoma (HCC) and other extrahepatic organ malignancies. The purpose of this study was to investigate whether MS and HBV have synergistic effects on cancers and to examine whether increasing the number of MS components could lead to higher risk of cancer development. Materials and Methods: We evaluated data from 1,504,880 HBV-infected adults who underwent a regular HCC screening program provided by the Korean National Health Insurance Service between 2009 and 2016. Results: The prevalence of MS in Korean HBV patients was 38.7% (582,449/1,504,880). Among individuals with HBV infection, the presence of MS was associated with an increased risk for the majority of malignancies except for HCC (HR = 0.862, p-value < 0.05). The presence of a higher number of MS components was associated with a significantly increased risk of developing cancers in most organs; only HCC was negatively associated with an increasing number of MS components (p < 0.01). Conclusions: Our data show that the presence of MS increases the risk for most malignancies, excluding HCC. Moreover, we found that as the number of MS components increased, the risk for most cancers also increased; this trend was reversed in HCC.

The Gut Microbiota: A Potential Gateway to Improved Health Outcomes in Breast Cancer Treatment and Survivorship.

Breast cancer is the most frequently diagnosed cancer in women worldwide. The disease and its treatments exert profound effects on an individual’s physical and mental health. There are many factors that impact an individual’s risk of developing breast cancer, their response to treatments, and their risk of recurrence. The community of microorganisms inhabiting the gastrointestinal tract, the gut microbiota, affects human health through metabolic, neural, and endocrine signaling, and immune activity. It is through these mechanisms that the gut microbiota appears to influence breast cancer risk, response to treatment, and recurrence. A disrupted gut microbiota or state of ‘dysbiosis’ can contribute to a biological environment associated with higher risk for cancer development as well as contribute to negative treatment side-effects. Many cancer treatments have been shown to shift the gut microbiota toward dysbiosis; however, the microbiota can also be positively manipulated through diet, prebiotic and probiotic supplementation, and exercise. The objective of this review is to provide an overview of the current understanding of the relationship between the gut microbiota and breast cancer and to highlight potential strategies for modulation of the gut microbiota that could lead to improved clinical outcomes and overall health in this population.

Differential risk of incident cancer in patients with heart failure: A nationwide population-based cohort study

BackgroundHeart failure (HF) and cancer are currently two leading causes of mortality, and sometimes coexist. However, the relationship between them is not completely elucidated. We aimed to investigate whether patients with HF are predisposed to cancer development using the large Korean National Health Insurance claims database. MethodsThis study included 128,441 HF patients without a history of cancer and 642,205 age- and sex-matched individuals with no history of cancer and HF between 1 January 2010 and 31 December 2015. ResultsDuring a median follow-up of 4.06 years, 11,808 patients from the HF group and 40,805 participants from the control were newly diagnosed with cancer (cumulative incidence, 9.2% vs. 6.4%, p < 0.0001). Patients with HF presented a higher risk for cancer development compared to controls in multivariable Cox analysis [hazard ratio (HR) 1.64, 95% confidence interval (CI) 1.61−1.68]. The increased risk was consistent for all site-specific cancers. To minimize potential surveillance bias, additional analysis was performed by eliminating participants who developed cancer within the initial 2 years of HF diagnosis (i.e. 2-year lag analysis). In the 2-year lag analysis, the higher risk of overall cancer remained significant in patients with HF (HR 1.09, 95% CI 1.05−1.13), although the association was weaker. Among the site-specific cancers, three types of cancer (lung, liver/biliary/pancreas, and hematologic malignancy) were consistently at higher risk in patients with HF. An exploratory analysis showed that patients with repeated HF hospitalization had a higher risk of cancer development compared to those without, in a pattern of stepwise increases across the three groups [controls vs. HF without re-hospitalization vs. HF with re-hospitalization ≥1; HR (95% CI), 1.00 (reference) vs. 1.55 (1.51–1.59) vs. 1.96 (1.89–2.03), respectively]. ConclusionsCancer incidence is higher in patients with HF than the general population. Active surveillance of coexisting malignancy needs to be considered in these patients.

Carotenoids in Cancer Apoptosis-The Road from Bench to Bedside and Back.

An incidence and mortality of cancer are rapidly growing worldwide, especially due to heterogeneous character of the disease that is associated with irreversible impairment of cellular homeostasis and function. Targeting apoptosis, one of cancer hallmarks, represents a potent cancer treatment strategy. Carotenoids are phytochemicals represented by carotenes, xanthophylls, and derived compounds such as apocarotenoids that demonstrate a broad spectrum of anti-cancer effects involving pro-apoptotic signaling through extrinsic and intrinsic pathways. As demonstrated in preclinical oncology research, the apoptotic modulation is performed at post-genomic levels. Further, carotenoids demonstrate additive/synergistic action in combination with conventional oncostatic agents. In addition, a sensitization of tumor cells to anti-cancer conventional treatment can be achieved by carotenoids. The disadvantage of anti-cancer application of carotenoids is associated with their low solubility and, therefore, poor bioavailability. However, this deficiency can be improved by using nanotechnological approaches, solid dispersions, microemulsions or biofortification that significantly increase the anti-cancer and pro-apoptotic efficacy of carotenoids. Only limited number of studies dealing with apoptotic potential of carotenoids has been published in clinical sphere. Pro-apoptotic effects of carotenoids should be beneficial for individuals at high risk of cancer development. The article considers the utility of carotenoids in the framework of 3P medicine.

De novo malignancy risk in patients undergoing the first percutaneous coronary intervention: A nationwide population-based cohort study

BackgroundAlthough percutaneous coronary intervention (PCI) has been the mainstay of revascularization strategy for significant coronary artery disease, future cancer risk after PCI has never been explored. We aimed to investigate the risk of incident cancer in patients undergoing PCI for the first time. MethodsWe studied 125,613 patients who underwent the first PCI between 2010 and 2015 without a prior history of cancer. For comparison, we selected 628,065 age- and sex-matched controls without any history of cancer or PCI who completed the assigned national health examination during the same period. ResultsDuring a median 4.56 years (interquartile range, 3.06–6.13 years), 8528 patients from the PCI group and 40,166 controls were newly diagnosed with cancer (incidence rate, 15.1 vs. 13.9 per 1000 person-years, p < 0.0001). Patients undergoing PCI presented a higher risk for cancer development than the controls in multivariable Cox analysis (adjusted HR [aHR] 1.06, 95% CI 1.04–1.09, p < 0.0001). To minimize potential surveillance bias, we performed 1-year lag analysis by eliminating participants who developed cancer within 1 year from the PCI. In this analysis, the increased risk of overall cancer in the PCI group became insignificant (aHR 1.02, 95% CI 0.99–1.05, p = 0.2017). Regarding site-specific cancers, however, the risk of lung and hematologic malignancies remained higher and the risk of gastrointestinal, liver/biliary/pancreas, thyroid, and breast cancers remained lower in the PCI group. ConclusionsDifferential future cancer risks were observed in patients undergoing PCI. The results suggest that specialized surveillance strategy might be warranted for this expanding population.

Abstract 1646: Beyond BRCA: Discovery of novel drivers of homologous recombination deficiencies in cancer

Abstract Since the discovery of BRCA1 and BRCA2 mutations as cancer risk factors, we have gained much understanding of their role in maintaining genomic stability through homologous recombination (HR) DNA repair. However, mutations in BRCA1/2 and other classical HR proteins such as RAD51 and PALB2 only identify 10-20% of TCGA patients who display HR deficiencies, indicating that we do not understand the vast majority of HR defects. Here, we leveraged the abundance of molecular characterization from TCGA patients for network analysis to fill this knowledge void. We discovered that over half of HR deficiencies originate outside of canonical DNA damage response genes, with particular enrichment for RNA binding proteins (RBPs). Experimental techniques validated over 90% of our predictions in a panel of 50 genes tested by siRNA, as well as 30/31 additional engineered mutations identified in TCGA patients. We further cross-validated these findings in independent patient cohorts, finding that the identified RNA processing mutations again enriched for HR deficient patients to an equal or greater degree than mutations in DNA damage genes. Using a series of experimental approaches, including protein interactome screening, RNA sequencing, and quantitative imaging cytometry, we probed how loss of RBP function induced global DNA damage response rewiring, including changes in RNA splicing, protein-protein interactions, and recruitment of repair factors to DNA damage sites. Clinically, defects in HR are known to promote cancer initiation, but also sensitize cells to targeted therapies such as PARP inhibition. We found that depletion RBPs from PARP-resistant triple-negative breast cancer cells induced sensitivity to multiple PARP inhibitors, indicating that this could identify new cohorts of patients who may benefit from PARP inhibition, beyond the small number of BRCA1/2-mutant patients. Moreover, we find that the identified RBP genes are significantly enriched for genes associated with cancer risk identified through GWAS. In patients, HR deficiencies were not equally distributed across all demographics, so preferential screening of those most at risk could further heighten this benefit. Thus, these novel drivers may show clinical relevance both for treatment stratification and for identifying individuals at high risk for cancer development to improve patient outcomes. Taken together, this exhaustive study greatly expands our repertoire of known drivers of HR deficiencies and mechanisms of damage repair, which may impact research from the most basic biology studies to clinical screening and stratification. Citation Format: Nidhi Sahni, Daniel McGrail, Yongsheng Li, Gordon Mills, Song (Stephen) Yi. Beyond BRCA: Discovery of novel drivers of homologous recombination deficiencies in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1646.

Prédisposition héréditaire au cancer du sein (1)

The main objective of oncogenetics is to characterize a subpopulation of patients at high risk of cancer development at an early age in order to provide specific recommendations for an optimized follow-up and care path. Oncogenetic counselling helps to assess individual risk from a family history. By a family approach of formal genetics, the key issue is to identify families with a strong aggregation of cancers, and, in particular, suggesting a specific syndrome of inherited predisposition to cancer. This approach can lead to the proposal of germline genetic testing in search of causal mutations. As up to know, the search for a constitutional mutation in the BRCA genes has led to the identification of a causal deleterious mutation in less than 10% of index-cases analyzed. It is therefore important to evaluate the impact of new genes in the current panorama of inherited predisposition to breast and ovarian cancer.