Increased Tumor Risk Research Articles

Sirolimus for vascular anomalies associated with PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a rare condition associated with vascular anomalies and increased tumor risk. Sirolimus, an mTOR inhibitor used for managing vascular anomalies is underexplored in PHTS. A single-institution retrospective review of children with PHTS and vascular anomalies treated with sirolimus identified seven patients. Median age at sirolimus initiation was 10years. After a median 2.5-year follow-up, six of seven patients (86%) showed significant clinical improvement. No significant adverse effects were observed, except mild buccal ulcers and acne. This study supports sirolimus as an effective and safe treatment for vascular anomalies in a small group of children with PHTS.

Correlation between large rearrangements and patient phenotypes in NF1 deletion syndrome: an update and review

About 5–10% of neurofibromatosis type 1 (NF1) patients exhibit large genomic germline deletions that remove the NF1 gene and its flanking regions. The most frequent NF1 large deletion is 1.4 Mb, resulting from homologous recombination between two low copy repeats. This “type-1” deletion is associated with a severe clinical phenotype in NF1 patients, with several phenotypic manifestations including learning disability, a much earlier development of cutaneous neurofibromas, an increased tumour risk, and cardiovascular malformations. NF1 adjacent co-deleted genes could act as modifier loci for the specific clinical manifestations observed in deleted NF1 patients. Furthermore, other genetic modifiers (such as CNVs) not located at the NF1 locus could also modulate the phenotype observed in patients with large deletions. In this study, we analysed 22 NF1 deletion patients by genome-wide array-CGH with the aim (1) to correlate deletion length to observed phenotypic features and their severity in NF1 deletion syndrome, and (2) to identify whether the deletion phenotype could also be modulated by copy number variations elsewhere in the genome. We then review the role of co-deleted genes in the 1.4 Mb interval of type-1 deletions, and their possible implication in the main clinical features observed in this high-risk group of NF1 patients.

Mobile phone use and brain tumour risk – COSMOS, a prospective cohort study

BackgroundEach new generation of mobile phone technology has triggered discussions about potential carcinogenicity from exposure to radiofrequency electromagnetic fields (RF-EMF). Available evidence has been insufficient to conclude about long-term and heavy mobile phone use, limited by differential recall and selection bias, or crude exposure assessment. The Cohort Study on Mobile Phones and Health (COSMOS) was specifically designed to overcome these shortcomings. MethodsWe recruited participants in Denmark, Finland, the Netherlands, Sweden, and the UK 2007–2012. The baseline questionnaire assessed lifetime history of mobile phone use. Participants were followed through population-based cancer registers to identify glioma, meningioma, and acoustic neuroma cases during follow-up. Non-differential exposure misclassification was reduced by adjusting estimates of mobile phone call-time through regression calibration methods based on self-reported data and objective operator-recorded information at baseline. Hazard ratios (HR) and 95% confidence intervals (CI) for glioma, meningioma, and acoustic neuroma in relation to lifetime history of mobile phone use were estimated with Cox regression models with attained age as the underlying time-scale, adjusted for country, sex, educational level, and marital status. Results264,574 participants accrued 1,836,479 person-years. During a median follow-up of 7.12 years, 149 glioma, 89 meningioma, and 29 incident cases of acoustic neuroma were diagnosed. The adjusted HR per 100 regression-calibrated cumulative hours of mobile phone call-time was 1.00 (95 % CI 0.98–1.02) for glioma, 1.01 (95 % CI 0.96–1.06) for meningioma, and 1.02 (95 % CI 0.99–1.06) for acoustic neuroma. For glioma, the HR for ≥ 1908 regression-calibrated cumulative hours (90th percentile cut-point) was 1.07 (95 % CI 0.62–1.86). Over 15 years of mobile phone use was not associated with an increased tumour risk; for glioma the HR was 0.97 (95 % CI 0.62–1.52). ConclusionsOur findings suggest that the cumulative amount of mobile phone use is not associated with the risk of developing glioma, meningioma, or acoustic neuroma.

Ceramides Increase Fatty Acid Utilization in Intestinal Progenitors to Enhance Stemness and Increase Tumor Risk

Cancers of the alimentary tract, including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia, are common comorbidities of obesity. Prolonged, excessive delivery of macronutrients to the cells lining the gut can increase one's risk for these cancers by inducing imbalances in the rate of intestinal stem cell proliferation vs differentiation, which can produce polyps and other aberrant growths. We investigated whether ceramides, which are sphingolipids that serve as a signal of nutritional excess, alter stem cell behaviors to influence cancer risk. We profiled sphingolipids and sphingolipid-synthesizing enzymes in human adenomas and tumors. Thereafter, we manipulated expression of sphingolipid-producing enzymes, including serine palmitoyltransferase (SPT), in intestinal progenitors of mice, cultured organoids, and Drosophila to discern whether sphingolipids altered stem cell proliferation and metabolism. SPT, which diverts dietary fatty acids and amino acids into the biosynthetic pathway that produces ceramides and other sphingolipids, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the sphingolipid biosynthesis pathway are up-regulated in human intestinal adenomas. They produce ceramides, which serve as prostemness signals that stimulate peroxisome-proliferator activated receptor-α and induce fatty acid binding protein-1. These actions lead to increased lipid utilization and enhanced proliferation of intestinal progenitors. Ceramides serve as critical links between dietary macronutrients, epithelial regeneration, and cancer risk.

Janus kinase inhibitors alter NK cell phenotypes and inhibit their antitumour capacity.

Janus kinase inhibitors (JAKi) are efficacious in RA but concerns regarding the risk of cancer associated with their exposure have recently emerged. Given the role of NK cells in antitumour response, we investigated the impact of JAKi [tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA) and filgotinib (FIL)] on NK cells. We first performed an ex vivo phenotype of NK cells in RA patients treated with TOFA, BARI or MTX. We next phenotyped sorted NK cells from healthy donors cultured with four JAKi or dimethyl sulphoxide (DMSO) at three concentrations, including the licensed dose (therapeutic concentration). Third, we assessed NK cell function using anti-NKp30 cross-linking and co-cultures with two different tumour cell lines: A549 and SU-DHL-4. Twenty-eight RA patients were included. Patients treated with TOFA had reduced expression of CD69 on NK cells compared with MTX (P < 0.05). We confirmed in vitro the negative impact of JAKi on NK cell maturation (CD57), activation (CD69) and activating receptor (NKp30), these latter two being specifically altered with TOFA and UPA. When NK cells were stimulated by NKp30, we observed reduced CD107a (P < 0.01) and IFN-γ/TNF expression (P < 0.05) with TOFA. Lastly, NK cells exposed to TOFA showed reduced CD107a (P < 0.05) and altered cytotoxicity (P < 0.05) when co-cultured with the two cell lines. JAKi have a phenotypic and functional impact on NK cell activation and impair their antitumour activity, with a variable impact depending on the JAKi. It remains an open question whether this mechanism can explain the increased tumour risk observed with TOFA.

Simpson-Golabi-Behmel Syndrome: A Case Report

Simpson-Golabi-Behmel syndrome (GBS) is a rare, X-linked recessive genetic disorder caused by loss-of-function mutations in the GPC3 (Xq26) gene, with polymorphic clinical presentation and evolutionary profile, characterized by growth accelerated pre- and postnatal, facial dysmorphism and visceral and skeletal malformations, varied and inconstant, as well as an increased tumor risk. We report the case of a 4-month-old infant, the result of a poorly followed pregnancy carried to term, birth weight was 4200g with notion of delayed cry. The parents are non-consanguineous, no similar case in the family. Our patient is followed for hemicorporal tonic-clonic epileptic seizures evolving since birth, controlled by phenobarbital. Clinical examination found psychomotor retardation, height and weight advance, macrocrania, enlarged anterior fontanelle, facial dysmorphism with hypertelorism and obliterated nasal root, supernumerary nipple, umbilical hernia and polydactyly. Examination of the external genitalia reveals cryptorchidism bilateral. A paraclinical assessment was requested to look for associated malformations came back normal. In the light of the literature and through this observation, the authors support the phenotypic, genetic and evolutionary particularities of the syndrome by Simpson-Golabi-Behmel.

The impact of body mass index and height on risk for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in 1.7 million norwegian women and men: a prospective cohort study

Background Primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves comprise a heterogenous group of pathology, dominantly represented by meningioma, nerve sheath tumours (NST) and glioma. Body height and body mass index (BMI) are risk factors for certain brain tumour subgroups, but no other study has specifically assessed height and BMI in relation to primary tumours of the spine and peripheral nerves in women and men. Methods In this prospective population-based cohort study height and weight were measured in 1.7 million adult Norwegian women and men at baseline. Incident cases of primary tumours arising from the spinal cord, spinal meninges, spinal and peripheral nerves during follow-up were identified by linkage to the National Cancer Registry. Tumour risk was assessed by Cox regression analyses in relation to height and BMI. Results During 49 million person-years of follow-up, 857 primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves were identified. Overweight and obesity were not associated with risk for all tumours or any tumour subgroup. Height was positively associated with risk for all tumours (HR per 10 cm increase: 1.30, 95% CI 1.16–1.46). The association between height and tumour risk varied between tumour subgroups: while height was not significantly associated with NST, height increased the risk for meningioma (HR 1.42, 95% CI 1.13–1.78) and glioma (HR 1.56, 95% CI 1.06–2.28). The strongest association between height and tumour risk was found for the glioma subgroup of ependymoma in women (HR 3.38, 95% CI 1.64–6.94). Conclusion This study could not identify overweight and obesity as risk factors for primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves in women or men. Increasing body height was associated with increased tumour risk overall, but not universal for all tumour subgroups. Importance of the study Primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves have received little focus in epidemiologic studies, although the incidence and histo-pathological tumour subgroups differ significantly from primary brain tumours. Risk factors for these tumours have hardly been assessed in previous studies. Height, overweight and obesity are known risk factors for several cancers, including certain brain tumour subgroups, such as meningioma. This is the first study to report the association between height, overweight and obesity and primary tumours of the spinal cord, spinal meninges, spinal and peripheral nerves. This includes tumour subgroups of meningioma, nerve sheath tumour, glioma and the most common spinal glioma subgroup of ependymoma. While overweight and obesity were not associated with either of the tumour subgroups, an association between increasing body height and risk for spinal meningioma and glioma, including ependymoma, was found. Nerve sheath tumour risk was not associated with increasing body height.

SOLITARY FIBROUS SARCOMA: LATE PRESENTATION WITH DIRE EFFECTS

TOPIC: Lung Cancer TYPE: Medical Student/Resident Case Reports INTRODUCTION: A 73-year-old woman with history of breast cancer status post radiation and chemotherapy was eval-uated in our emergency department (ED) for left sided chest pain that worsened over the previous month. She had two weeks of progressive physical limitation, and developed orthopnea the night prior which prompted her to seek care. CASE PRESENTATION: In the ED she was noted to have unrelenting left sided pleuritic chest pain. Physical exam was nota-ble for diminished breath sounds on the left side. Computed tomography (CT) scan of her chest re-vealed a 9.7 x 5.5 cm left lung mass with an associated complex loculated effusion. A left sided chest tube was placed for the loculated pleural effusion. It was exudative by Light's criteria, and pleural flu-id hematocrit was consistent with a hemothorax. She underwent a biopsy of the left lung mass which demonstrated CD34, BCL2, STAT6, spindle cell features and staghorn vasculature indicating a ma-lignant solitary fibrous sarcoma (SFS). She eventually underwent resection as an outpatient once staging confirmed no distant metastatic disease. DISCUSSION: The majority of thoracic solitary fibrous tumors (SFTs) are asymptomatic benign intrathoracic masses discovered incidentally on chest imaging. SFS are a malignant subtype of SFT [1]. Our case demon-strates a rare finding of a large left sided malignant solitary fibrous sarcoma that presented with a large hemothorax. SFTs generally arise from CD34+ dendritic mesenchymal cells which are present in nearly all connective tissues [2]. Association with pleural effusion may be associated with an in-creased risk of a malignant tumor [3]. The presence of a hemothorax has also been reported to cor-relate with rapid tumor enlargement [3]. STAT6, CD34, BCL2 are the most commonly found positive markers, with STAT6 sensitivity being reported as high as 100% [4]. CONCLUSIONS: Our patient did have a history of radiation treatment for left sided breast cancer which has been im-plicated in the development of SFS, particularly in the same radiation fields [5, 6]. Prognosis is usual-ly unpredictable with surgery being the gold standard in treatment [7]. In malignant tumors, chemo-therapy and radiation have limited efficacy [7]. Recurrence rates in malignant SFS are high even with complete resection, reported to be around 63% [8]. REFERENCE #1: Davanzo B, Emerson RE, Lisy M, Koniaris LG, Kays JK. Solitary fibrous tumor. Transl Gastroente-rol Hepatol. 2018 Nov 21;3:94. doi: 10.21037/tgh.2018.11.02. PMID: 30603730; PMCID: PMC6286917. REFERENCE #2: Zuo Z, Zhou H, Sun Y, Mao Q, Zhang Y, Gao X. Rapidly growing solitary fibrous tumors of the pleura: a case report and review of the literature. Ann Transl Med. 2020 Jul;8(14):890. doi: 10.21037/atm-20-4974. PMID: 32793734; PMCID: PMC7396790. REFERENCE #3: Tan JH, Hsu AA. Challenges in diagnosis and management of giant solitary fibrous tumour of pleu-ra: a case report. BMC Pulm Med 2016;16:114. 10.1186/s12890-016-0279-0. REFERENCE #4: Zhang P, Xiong K, Lv P, et al. Malignant solitary fibrous tumor occurring in the mediastinal pleura showing NAB2ex4-STAT6ex2 fusion and negative STAT6 immunohistochemistry: A case report. Thorac Cancer 2020;11:1344-9. 10.1111/1759-7714.13395. REFERENCE #5: Rubino C, Shamsaldin A, Lê MG, Labbé M, Guinebretière JM, Chavaudra J, de Vathaire F. Radia-tion dose and risk of soft tissue and bone sarcoma after breast cancer treatment. Breast Cancer Res Treat. 2005;89(3):277–288. doi: 10.1007/s10549-004-2472-8. REFERENCE #6: Karlsson P, Holmberg E, Johansson KA, Kindblom LG, Carstensen J, Wallgren A. Soft tissue sar-coma after treatment for breast cancer. Radiother Oncol. 1996;38(1):25–31. doi: 10.1016/0167-8140(95)01663-5. REFERENCE #7: Ronchi et al., "Extrapleural Solitary Fibrous Tumor: A Distinct Entity from Pleural Solitary Fibrous Tumor. An Update on Clinical, Molecular and Diagnostic Features. REFERENCE #8: Boothe JT, Budd GT, Smolkin MB, et al. Durable Near-Complete Response to Anti-PD-1 Check-point Immunotherapy in a Refractory Malignant Solitary Fibrous Tumor of the Pleura. Case Rep Oncol 2017;10:998-1005. 10.1159/000484041. DISCLOSURES: No relevant relationships by Danish Ahmad, source=Web Response No relevant relationships by Saad Ashraf, source=Web Response No relevant relationships by Fiyad Haniff, source=Web Response no disclosure on file for Jennifer Toth

PD45-07 RISK OF RECURRENCE AND SURVIVAL OF DIALYZED AND TRANSPLANT PATIENTS WITH RENAL CELL CARCINOMA OF NATIVE KIDNEYS

You have accessJournal of UrologyRenal Transplantation & Vascular Surgery II (PD45)1 Sep 2021PD45-07 RISK OF RECURRENCE AND SURVIVAL OF DIALYZED AND TRANSPLANT PATIENTS WITH RENAL CELL CARCINOMA OF NATIVE KIDNEYS Jorge Correia, Mariana Madanelo, Sofia Mesquita, Gonçalo Mendes, Avelino Fraga, and Miguel Silva-Ramos Jorge CorreiaJorge Correia More articles by this author , Mariana MadaneloMariana Madanelo More articles by this author , Sofia MesquitaSofia Mesquita More articles by this author , Gonçalo MendesGonçalo Mendes More articles by this author , Avelino FragaAvelino Fraga More articles by this author , and Miguel Silva-RamosMiguel Silva-Ramos More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002059.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Renal transplantation requires immunosuppression, which was regarded as a risk factor for tumor progression in all types of malignancy. Therefore, until recently, based on the Cincinnati registry a waiting period before transplantation was mandatory in any patient with a history of cancer. However, this registry doesn’t take into account current staging, disease biology or advances in treatments, and there is growing evidence that the increased tumor risk by immunosuppression is restricted to particular subgroups of malignancy, whereas others such as renal cell carcinoma (RCC) are not negatively influenced. Our objective was to compare the risk of recurrence of RCC of native kidneys and death in patients with end-stage renal disease (ESRD), according to their dialysis or transplantation status. METHODS: We performed a retrospective analysis of all patients with ESRD diagnosed with RCC between 2010 and 2019 in our center, and stratified them according to their dialysis (D) or kidney transplantation (KT) status.Patients’ characteristics were compared by using Chi-square (or Fischer) and t-tests. Survival was assessed by Kaplan-Meier and Cox proportional hazards model. RESULTS: 40 patients were followed for a median of 41 months [IQR 22-71], 22 KT and 18 D. KT had a lower ASA score (p<0.001) and lower grade of tumor (p=0.014). All other clinical and pathological characteristics were similar between groups. The risk of RCC recurrence was similar between them (HR=0.402; p=0.458). 5-year recurrence-free survival was 96% in KT and 89% in D (p=0.443). All recurrences were on the contralateral kidney, without impact on patient or graft survival. In multivariable Cox regression analysis, no predictor was significantly associated with the risk of recurrence, including presence of KT. No cancer-related deaths were seen during follow-up, with the majority of deaths being related to cardiovascular disease (100% in KT and 60% in D). 5-year overall survival was 91% and 72% for KT and D, respectively (p=0.181). KT did not have a lower survival compared to D patients (HR=0.343; p=0.202). In multivariable analysis the presence of a renal transplant had no effect on survival (HR=0.002; p=0.167). Time on dialysis was the only independent predictor of overall survival (HR=1.058; p=0.049). CONCLUSIONS: Most RCCs in renal transplant recipients are low-grade and exhibit many favorable pathological characteristics. Immunosuppression doesn’t seem to have an impact on outcomes, but an increased time on dialysis seems to be associated with worse survival. As so, waiting time for low stage/low grade RCC could be reduced. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e744-e745 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jorge Correia More articles by this author Mariana Madanelo More articles by this author Sofia Mesquita More articles by this author Gonçalo Mendes More articles by this author Avelino Fraga More articles by this author Miguel Silva-Ramos More articles by this author Expand All Advertisement Loading ...

Reprogramming enriches for somatic cell clones with small-scale mutations in cancer-associated genes

Cellular therapies based on induced pluripotent stem cells (iPSCs) come out of age and an increasing number of clinical trials applying iPSC-based transplants are ongoing or in preparation. Recent studies, however, demonstrated a high number of small-scale mutations in iPSCs. Although the mutational load in iPSCs seems to be largely derived from their parental cells, it is still unknown whether reprogramming may enrich for individual mutations that could lead to loss of functionality and tumor formation from iPSC derivatives. 30 hiPSC lines were analyzed by whole exome sequencing. High accuracy amplicon sequencing showed that all analyzed small-scale variants pre-existed in their parental cells and that individual mutations present in small subpopulations of parental cells become enriched among hiPSC clones during reprogramming. Among those, putatively actionable driver mutations affect genes related to cell-cycle control, cell death, and pluripotency and may confer a selective advantage during reprogramming. Finally, a short hairpin RNA (shRNA)-based experimental approach was applied to provide additional evidence for the individual impact of such genes on the reprogramming efficiency. In conclusion, we show that enriched mutations in curated onco- and tumor suppressor genes may account for an increased tumor risk and impact the clinical value of patient-derived hiPSCs.

Generation of Systemic Lupus Erythematosus Patient-Derived Induced Pluripotent Stem Cells from Blood.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by the production of multiple autoimmune antibodies and potentially involves any organ or tissue with a broad range of clinical manifestations. Conventional therapy still utilizes glucocorticoids and immunosuppressants. However, some patients show inadequate responses to glucocorticoids and immunosuppression, which may induce secondary immune dysfunction and severe infection as well as lead to an increased tumor risk. The lack of in vitro models has hampered progress in understanding and treating SLE. Patient-derived induced pluripotent stem cells (iPSCs) may provide a unique opportunity for modeling in vitro diseases as well as a platform for drug screening in individual patients. We isolated peripheral blood mononuclear cells from blood to explore the establishment of an in vitro model platform for SLE and directly purified CD34+ cells and seeded them for expansion. CD34+ cells were forced to express seven pluripotency factors, OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT, through transduction in lentiviral vectors. The morphological characteristics of induced pluripotent stem-like cells, such as prominent nucleoli and a high nucleus-to-cytoplasm ratio, were observed. The pluripotency of established SLE patient-derived iPSCs was confirmed by the expression of embryonic stem cell (ESC) markers and the ability of cells to differentiate into multiple cell lines. SLE patient-derived iPSCs exhibited human ESC properties, including morphology; growth characteristics; expression of pluripotency, genes, and surface markers; and teratoma formation. In conclusion, we generated SLE patient-derived iPSCs and validated their pluripotency. This study is a first but critical step that can provide a model platform for research aimed at understanding the SLE mechanism, which may lead to the discovery of new targets or compounds for the treatment of this disease.

Cellular Phone Use and Risk of Tumors: Systematic Review and Meta-Analysis.

We investigated whether cellular phone use was associated with increased risk of tumors using a meta-analysis of case-control studies. PubMed and EMBASE were searched from inception to July 2018. The primary outcome was the risk of tumors by cellular phone use, which was measured by pooling each odds ratio (OR) and its 95% confidence interval (CI). In a meta-analysis of 46 case-control studies, compared with never or rarely having used a cellular phone, regular use was not associated with tumor risk in the random-effects meta-analysis. However, in the subgroup meta-analysis by research group, there was a statistically significant positive association (harmful effect) in the Hardell et al. studies (OR, 1.15—95% CI, 1.00 to 1.33— n = 10), a statistically significant negative association (beneficial effect) in the INTERPHONE-related studies (case-control studies from 13 countries coordinated by the International Agency for Research on Cancer (IARC); (OR, 0.81—95% CI, 0.75 to 0.89—n = 9), and no statistically significant association in other research groups’ studies. Further, cellular phone use with cumulative call time more than 1000 h statistically significantly increased the risk of tumors. This comprehensive meta-analysis of case-control studies found evidence that linked cellular phone use to increased tumor risk.

Long-term exposure to \u201clow-dose\u201d bisphenol A decreases mitochondrial DNA copy number, and accelerates telomere shortening in human CD8\u2009+\u2009T cells

Exposure to the endocrine disruptor bisphenol A (BPA) has been linked with immune disorders and increased tumour risk. Our previous work in activated human peripheral blood mononuclear cells demonstrated that exposure to “low-dose” BPA diminished telomerase activity via an ER/GPR30-ERK signalling pathway. Leukocyte telomerase activity and telomere maintenance are crucial for normal immune function and homeostasis. We thus here further studied the effects of BPA on human T cell subpopulations. Exposure to 0.3–3 nM BPA, i. e. at doses in the realm of human exposure, notably reduced telomerase activity in activated CD8 + T but not CD4 + T cells in a non-monotonic response pattern as determined by the TRAP-ELISA assay. Under long-term BPA exposure, significant telomere length shortening, reduction in mitochondrial DNA copy number, cell proliferation and IFN-γ as well as hTERT protein suppression could be observed in CD8 + lymphocytes, as analysed by qRT-PCR, flow cytometry and western blot analysis. This study extends our previous in vitro findings that “low-dose” BPA has potential negative effects on healthy human cytotoxic T cell response. These results might merit some special attention to further investigate chronic BPA exposure in the context of adaptive immune response dysfunction and early onset of cancer in man.

Turner Syndrome with Y Chromosome: Spontaneous Thelarche, Menarche, and Risk of Malignancy.

Girls with Turner syndrome with Y-chromosome material (TS+Y) are assumed to have nonfunctional gonads with increased tumor risk, therefore prophylactic gonadectomy is recommended at diagnosis. In this study we aimed to determine rates of spontaneous thelarche (ST) and spontaneous menarche (SM), and prevalence of gonadal tumor and malignancy in girls with TS+Y, to further inform discussions about gonadectomy. Retrospective review of clinical and pathology data. Multicenter study involving 4 United States children's hospitals. Patients included those with a genetically proven diagnosis of TS+Y and phenotypically female genitourinary exam. Demographic characteristics, pubertal development, and gonadal pathology data were abstracted from clinical records. Data for ST were analyzed for patients aged 13years and older and SM for patients older than 15years. ST, SM, prevalence of gonadal tumor, and malignancy. Forty-four patients met inclusion criteria. Nineteen patients were 13years or older; 8/19 (42%) had ST and reached Tanner stages 2-4 and 2 (11%) had normal ovarian pathology. Nineteen patients were 15years or older; 2/19 (11%) had SM. Thirty-seven patients underwent gonadectomy; 35 had available pathology results. Gonadoblastoma was identified in 35/7 patients (19%), 1 in situ germ cell neoplasia, and 1 dysgerminoma (3%). One patient with bilateral gonadoblastoma had ST and SM. In this multicenter cohort, 42% of girls with TS+Y entered puberty spontaneously and 11% had SM, supportive of gonadal function. Risk of tumor was similar to previous reports. To achieve informed decision-making, discussions about gonadectomy should incorporate potential for gonadal function and tumor risk.

Dissecting TSC2-mutated renal and hepatic angiomyolipomas in an individual with ARID1B-associated intellectual disability

BackgroundSeveral subunits of the SWI/SNF chromatin remodeling complex are implicated in both cancer and neurodevelopmental disorders (NDD). Though there is no clinical evidence for an increased tumor risk in individuals with NDDs due to germline mutations in most of these genes so far, this has been repeatedly proposed and discussed. A young woman with NDD due to a de novo mutation in ARID1B now presented with a large renal (> 19 cm in diameter) and multiple hepatic angiomyolipomas (AMLs) but no other signs of tuberous sclerosis complex.MethodsWe analyzed tumor and healthy tissue samples with exome and panel sequencing.ResultsAdditionally to the previously known, germline ARID1B variant we identified a post-zygotic truncating TSC2 variant in both renal and hepatic AMLs but not in any of the healthy tissues. We did not detect any further, obvious tumor driver events. The identification of a passenger variant in SIPA1L3 in both AMLs points to a common clonal origin. Metastasis of the renal AML into the liver is unlikely on the basis of discordant histopathological features. Our findings therefore point to very low-grade mosaicism for the TSC2 variant, possibly in a yet unknown mesenchymal precursor cell that expanded clonally during tumor development. A possible contribution of the germline ARID1B variant to the tumorigenesis remains unclear but cannot be excluded given the absence of any other evident tumor drivers in the AMLs.ConclusionThis unique case highlights the blurred line between tumor genetics and post-zygotic events that can complicate exact molecular diagnoses in patients with rare manifestations. It also demonstrates the relevance of multiple disorders in a single individual, the challenges of detecting low-grade mosaicisms, and the importance of proper diagnosis for treatment and surveillance.

Genetic predisposition to childhood cancer

Tackling the topic of genetic predisposition to childhood cancer requires close co-operation between pathologists, pediatric oncologists, and human geneticists. It is not just about the precise diagnosis and the most effective treatment of the cancer, but also to prevent further cancerous diseases for those affected and also their family members. On the basis of examples such as Li-Fraumeni syndrome, constitutional mismatch repair deficiency (CMMRD), medullo- and neuroblastoma, as well as hematological neoplasias, we will discuss the criteria for tumor predisposition genetic syndromes, the relationship between somatic and germline variants, and the immediate clinical consequences. In some cases, the diagnosis of agenetic tumor predisposition syndrome has immediate consequences for the treatment, e. g. to avoid radiotherapy for Li-Fraumeni syndrome, which would otherwise significantly increase the probability of secondary, independent tumors. Predictive diagnostics can be offered to identify the family members who carry the pathogenic variant. Because of their increased tumor risk, they should be integrated into cancer surveillance programs. Evidence-based data show that this significantly improves overall survival.

Beckwith-Wiedemann Syndrome (BWS) Current Status of Diagnosis and Clinical Management: Summary of the First International Consensus Statement

Beckwith-Wiedemann syndrome (BWS) belongs to the group of imprinting disorders and is characterized by variable clinical features, including overgrowth, macroglossia, abdominal wall defect, neonatal hypoglycemia, body asymmetry and an increased risk for embryonal tumors. In the majority of cases, molecular alterations of the Imprinting Center (IC) regions in the chromosomal region 11p15.5 can be detected, and a correlation of single clinical features with specific genomic and epigenetic changes is obvious. Therefore, the detailed molecular diagnosis is a prerequisite for a precise prediction of the tumor risk and the tumor spectrum. Furthermore, it is the basis for a well-directed genetic counselling of the families. Despite a huge number of comprehensive studies based on a large number of cases, standardized diagnostic criteria and advices for therapeutic management were missing. In the following, the recently published first international consensus guidelines drafted by 41 experts in the field of BWS from 11 European countries and the USA are summarized. Patients support groups had been included as well. In total, 72 consented recommendations for clinical and molecular diagnosis as well as for the clinical management of BWS have been published. They refer both to patients with the classical BWS phenotype and to those with "atypical" phenotypes which are summarized as BWS spectrum (BWSp). A modified clinical scoring system is now suggested, which represents the basis to initiate molecular diagnostics. Therapeutic recommendations comprise the major clinical questions in BWS/BWSp, i. e. early monitoring of an increased tumor risk, treatment of the macroglossia and the abdominal wall defects, and therapeutic interventions for hypoglycemia. However, though there was a broad consensus on the majority of therapeutic interventions, discussions on tumor monitoring are foreseeable. Thus, prospective studies to evaluate the consensus guidelines and their use are planned.

Identification of a PTEN mutation with reduced protein stability, phosphatase activity, and nuclear localization in Hong Kong patients with autistic features, neurodevelopmental delays, and macrocephaly.

PTEN is a tumor suppressor gene inactivated in over 30% of human cancers. It encodes a lipid phosphatase that serves as a gatekeeper of the phosphoinositide 3‐kinase signaling pathway. Germline mutation frequently occurs in this gene in patients diagnosed with PTEN Hamartoma Tumor Syndrome (PHTS). PHTS individuals are characterized by macrocephaly, benign growth of multiple tissues and increased tumor risk. In addition, autistic phenotypes are found in 10–20% of individuals carrying the germline PTEN mutation with macrocephaly. In this report, 13 suspected PHTS patients were screened for mutation in the PTEN gene. A missense variant (c. 302T > C) substituting the isoleucine at codon 101 to a threonine, a single nucleotide insertion (c. 327‐328insC) causing a frame shift mutation and termination at codon 109, and a nonsense variant (c. 1003C > T) truncated the protein at codon 335 were identified. The I101T mutation significantly reduced PTEN protein expression levels by 2.5‐ to 4.0‐fold. Mechanistically, I101T reduced the protein half‐life of PTEN possibly due to enhanced polyubiquitination at Lysine 13. However, the I101T mutant retained almost 30% of the lipid phosphatase activity of the wild‐type protein. Finally, the I101T mutant has reduced phosphorylation at a PTEN auto‐dephosphorylation site at Threonine 366 and a lowered ratio of nuclear to cytosolic protein level. These partial losses of multiple PTEN biochemical functions may contribute to the tissue overgrowth and autistic features of this PHTS patient. Autism Res 2018, 11: 1098–1109. © 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc.Lay SummaryThe genetics of autism spectrum disorders is highly complex with individual risk influenced by both genetic and environmental factors. Mutation in the human PTEN gene confers a high risk of developing autistic behavior. This report revealed that PTEN mutations occurred in 23% of a selected group of Hong Kong patients harboring autistic features with gross overgrowth symptoms. Detailed characterization of a PTEN mutation revealed reduced protein stability as one of the underlying mechanisms responsible for reduced PTEN activity.

Circadian clocks and breast cancer.

Circadian clocks respond to environmental time cues to coordinate 24-hour oscillations in almost every tissue of the body. In the breast, circadian clocks regulate the rhythmic expression of numerous genes. Disrupted expression of circadian genes can alter breast biology and may promote cancer. Here we overview circadian mechanisms, and the connection between the molecular clock and breast biology. We describe how disruption of circadian genes contributes to cancer via multiple mechanisms, and link this to increased tumour risk in women who work irregular shift patterns. Understanding the influence of circadian rhythms on breast cancer could lead to more efficacious therapies, reformed public health policy and improved patient outcome.

Germline Genetics of the p53 Pathway Affect Longevity in a Gender Specific Manner

Aging is thought to occur through the accumulation of molecular and cellular damage. A key regulator of the cell's stress response is p53. In mice, the activity of p53 associates with lifespan. We were therefore interested whether SNPs in members of the p53-pathway are associated with longevity in humans. We genotyped the following SNPs: p53 - rs1042522 (Arg72Pro), MDM2 - rs2279744 (SNP309), MDM4 - rs4245739 (SNP34091), rs1563828 (SNP31826), PPP2R2B (rs319217) in 155 long-lived individuals (LLIs) who died at the age of 91 and over and in 171 ethnically-matched control subjects. Kaplan-Meier survival curves and log-Rank-test were used to determine the mean and median survival times. In female LLIs, the Pro-allele of rs1042522 (Arg72Pro) and the G-allele of rs2279744 (SNP309) were significantly associated with an increased survival time (P=0.026, P<0.001, respectively, log-Rank-test). In contrast, there was no difference regarding the survival time in male LLIs (rs1042522: P=0.58, rs2279744: P=0.503, log-Rank-test). There was no difference regarding the average age of death for the genotypes of the respective SNPs in the MDM4 gene (rs1563828: P=0.99; rs4245739: P=0.179, respectively). Here we show for the first time that the G-allele of rs2279744 (SNP309) is associated with increased lifespan. Importantly, this effect is gender-specific. Our data support the hypothesis that genetic variants that are associated with lower activity of p53--and therefore increased tumor risk--are associated with prolonged lifespan in a gender-specific manner.