Real-life clinical practice in Spain in the setting of new drug availability for ITP treatment. A Delphi-based Spanish expert panel consensus.

Immune thrombocytopenia (ITP) is a common autoimmune hematological disorder. Despite this, diagnosis is still challenging due to clinical heterogeneity and the lack of a specific diagnostic test. New findings in the pathology and the availability of new drugs have led to the development of different guidelines worldwide. In the present study, the Delphi methodology has been used to get a consensus on the management of adult patients with ITP in Spain and to help in decision-making. The Delphi questionnaire has been designed by a scientific ad hoc committee and has been divided into 13 topics, with a total of 127 items, covering the maximum possible scenarios for the management of ITP. As a result of the study, a total consensus of 81% has been reached. It is concluded that this Delphi consensus provides practical recommendations on topics related to diagnosis and management of ITP patients to help doctors to improve outcomes. Some aspects remain unclear, without consensus among the experts. Thus, more advances are needed to optimize ITP management.

What is the context? Immune thrombocytopenia (ITP) is a hematologic autoimmune disease characterized by accelerated destruction and inadequate production of platelets mediated by autoantibodies (platelet count <100 × 10⁹ /L).Despite being a common condition, its heterogeneous clinical course makes its diagnosis and management still a challenge.In recent years, new molecules with different mechanisms of action have emerged for the treatment of ITP.Due to the increasing information about the pathology and its therapies, several international guidelines have recently been established to provide recommendations for the management and treatment of ITP.There are still many patient scenarios and disease aspects which are not addressed in the guidelines.What is new? Our Spanish ITP Expert Group has developed a Delphi consensus study to provide recommendations and promote standardization of the management of adult patients with ITP in Spain.The scientific committee defined 127 statements for consensus, corresponding to 13 chapters: (i) Diagnosis of ITP, (ii) First-line treatment, (iii) Second-line treatment, (iv) Treatment of refractory patients, (v) Follow-up, (vi) Emergency and surgery, (vii) ITP in the elderly, (viii) ITP in pregnancy, (ix) Anticoagulation and antiplatelet, (x) Secondary ITP, (xi) Quality of life, (xii) Discontinuation of TPO-RA, and (xiii) ITP and Covid.The total number of agreed statements achieved was 103, giving a final percentage of consensus in the Delphi questionnaire of 81%.What is the impact? This Delphi consensus provides recommendations based on real clinical practice data, regarding the diagnosis, treatment, and management of patients and scenarios in ITP to assist clinicians in addressing this disease and achieving optimal outcomes for the patient.

Primary and secondary immune thrombocytopenia (ITP): Time for a rethink.

There are not many publications that provide a holistic view of the management of primary and secondary ITP as a whole, reflecting the similarities and differences between the two. Given the lack of major clinical trials, we believe that comprehensive reviews are much needed to guide the diagnosis and treatment of ITP today. Therefore, our review addresses the contemporary diagnosis and treatment of ITP in adult patients. With respect to primary ITP we especially focus on establishing the management of ITP based on the different and successive lines of treatment. Life-threatening situations, "bridge therapy" to surgery or invasive procedures and refractory ITP are also comprehensively reviewed here. Secondary ITP is studied according to its pathogenesis by establishing three major differential groups: Immune Thrombocytopenia due to Central Defects, Immune Thrombocytopenia due to Blocked Differentiation and Immune Thrombocytopenia due to Defective Peripheral Immune Response. Here we provide an up-to-date snapshot of the current diagnosis and treatment of ITP, including a special interest in addressing rare causes of this disease in our daily clinical practice. The target population of this review is adult patients only and the target audience is medical professionals.

Recommendations on the Management of Patients with Immune Thrombocytopenia (ITP) in the Context of SARS-CoV-2 Infection and Vaccination: Consensus Guidelines from a Spanish ITP Expert Group.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease with highly variable presentation, characteristics, and clinical course. Thrombocytopenia is a common complication of many viral infections, including SARS-CoV-2. In addition, both de novo ITP and exacerbation of ITP after vaccination against SARS-CoV-2 have been reported. Patients infected with SARS-CoV-2 develop a prothrombotic coagulopathy called COVID-19-associated coagulopathy (CAC). In addition, autoimmune hematological disorders secondary to SARS-CoV-2 infection, mainly ITP and autoimmune hemolytic anemia (AIHA), have been described. Furthermore, SARS-CoV-2 infection has been associated with exacerbation of autoimmune processes, including ITP. In fact, there is evidence of a high relapse rate in patients with preexisting ITP and COVID-19. As for vaccination against SARS-CoV-2, hematological adverse events (HAE) are practically anecdotal. The most common HAE is thrombocytopenia-associated thrombosis syndrome (TTS) linked to vectored virus vaccines. Other HAEs are very rare, but should be considered in patients with previous complement activation disease or autoimmunity. In patients with ITP who are vaccinated against SARS-CoV-2, the main complication is exacerbation of ITP and the bleeding that may result. In fact, this complication occurs in 12% of patients, with splenectomized and refractory patients with more than five lines of previous treatment and platelet counts below 50 × 109/L being the most vulnerable. We conclude that, in general, there is no greater risk of severe SARS-CoV-2 infection in ITP patients than in the general population. Furthermore, no changes are advised in patients with stable ITP, the use of immunosuppressants is discouraged unless there is no other therapeutic option, and patients with ITP are not contraindicated for vaccination against COVID-19.

Factor Validity of Measurement for Burnout in Chilean Prison Officers / Medida de Validez Factorial para el Burnout en Oficiales de Prisiones Chilenas

Abstract The objective of this research was to perform the factorial validity of the Maslach Burnout Inventory Human Services (MBIHSS) in prison officers in Chile through a first-order factor analysis and a confirmatory analysis. The sample was constituted by all the prison officers in the Region of Arica and Parinacota (N=334). Of these, 44 did not participate in the study, since they were in a medical leave, vacation or special permit, transfer in progress, or similar situation. Therefore, the final number of participants was 290 subjects. The Burnout Syndrome (BS) was estimated through the adaptation to Spanish (Gil-Monte, 2005) of the Maslach Burnout Inventory, in its version for human services professionals (MBI-HSS) (Maslach & Jackson, 1986), validated in Chile (Olivares, 2009). By way of conclusion, the present investigation found similarities in the MBI-HSS in terms of dimensionality and reliability analysis, and despite the international observations of the instrument, an adjusted proposal (standardization and validation) of the MBI-HSS is provided for contexts Prisoners with 18 items, since in Chile there is no validation of the MBI-HSS in prison officers;

Resumen El objetivo de esta investigación fue realizar la validez factorial de Maslach Burnout Inventory Human Services (MBIHSS) en funcionarios de prisiones en Chile a través de un análisis factorial de primer orden y un análisis confirmatorio. La muestra estuvo constituida por todos los funcionarios penitenciarios de la Región de Arica y Parinacota (N=334). De estos, 44 no participaron en el estudio, ya que se encontraban en un permiso médico, vacaciones o permiso especial, transferencia en curso o situación similar. El número final de participantes, por lo tanto, fue de 290 sujetos. El Sindrome de Burnout (BS) se estimò mediante la adaptación al espanol (Gil-Monte, 2005) del Maslach Burnout Inventory, en su versión para profesionales de servicios humanos (MBI-HSS) (Maslach & Jackson, 1986), validado en Chile (Olivares, 2009). A modo de conclusión, la presente investigación encontró similitudes en el MBI-HSS en términos de análisis de dimensionalidad y confiabilidad, y a pesar de las observaciones internacionales del instrumento, se proporciona una propuesta ajustada (estandarización y validación) del MBI-HSS para contextos Prisioneros con 18 items, ya que en Chile no hay validación del MBI-HSS en los funcionarios de prisiones

Wilson Disease Prevalence: Discrepancy Between Clinical Records, Registries and Mutation Carrier Frequency.

OBJECTIVES: Diagnosis of Wilson disease (WD) is difficult and, as early detection may prevent all symptoms, it is essential to know the exact prevalence to evaluate the cost-efficacy of a screening program. As the number of WD patients was high in our population, we wished to estimate prevalence by determining the carrier frequency for clinically relevant ATP7B mutations. METHODS: To estimate prevalence, screening for the most prevalent mutation was performed in 1661 individuals with ancestry in Gran Canaria, and the frequency of other mutations was estimated from patient records. Alternatively, ATP7B mutations were detected from exomes and genomes from 851 individuals with Canarian ancestry, 236 from Gran Canaria, and a public Spanish exome database. RESULTS: Estimated carrier frequencies in Gran Canaria ranged from 1 in 20 to 28, depending on the method used, resulting in prevalences of 1 case per 1547 to 3140 inhabitants. Alternatively, the estimated affected frequencies were 1 in 5985 to 7980 and 1 in 6278 to 16,510 in the archipelago or mainland Spain respectively. CONCLUSIONS: The number of carriers predicts much higher prevalences than reported, suggesting that WD is underdiagnosed; specific mutations may remain unnoticed due to low penetrance or no signs of disease at all; regional prevalence rather than national prevalence should be considered in cost-efficacy models to approach preventive screening in the asymptomatic population and genetic screening strategies will have to deal with the genetic heterogeneity of ATP7B in the general population and in patients.

Fotoféresis extracorpórea y trasplante renal / Extracorporeal photopheresis and renal transplantation

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Association between Heavy Metals and Rare Earth Elements with Acute Ischemic Stroke: A Case-Control Study Conducted in the Canary Islands (Spain).

The role of inorganic elements as risk factors for stroke has been suggested. We designed a case-control study to explore the role of 45 inorganic elements as factors associated with stroke in 92 patients and 83 controls. Nineteen elements were detected in >80% of patients and 21 were detected in >80% of controls. Blood level of lead was significantly higher among patients (11.2 vs. 9.03 ng/mL) while gold and cerium were significantly higher among controls (0.013 vs. 0.007 ng/mL; and 18.0 vs. 15.0 ng/mL). Lead was associated with stroke in univariate and multivariate analysis (OR = 1.65 (95% CI, 1.09-2.50) and OR = 1.91 (95% CI, 1.20-3.04), respectively). Gold and cerium showed an inverse association with stroke in multivariate analysis (OR = 0.81 (95% CI, 0.69-0.95) and OR = 0.50 (95% CI, 0.31-0.78)). Future studies are needed to elucidate the potential sources of exposure and disclose the mechanisms of action.

Direct and indirect effects of transformational leadership on volunteers' intention to remain at non-profit organizations / Los efectos directos e indirectos del liderazgo transformacional en la intención de los voluntarios de permanecer en organizaciones sin ánimo de lucro

Literature on leadership has provided sufficient evidence that leadership styles increase satisfaction, commitment, and retention of employees. However, there are few studies on the effects of leadership styles on volunteers. This study aims to investigate the possible influence of transformational leadership style on retention of volunteers. Our first hypothesis is that if a volunteer coordinator has a transformational leadership style, there is a higher intention to remain. Our second hypothesis is that this relationship is mediated by the variables of the three-stage model of volunteers' duration of service (satisfaction, organizational commitment, and role identity). To test these hypotheses, a sample of 417 volunteers (73% women), from 17 non-profit organizations, with an average age of 44 years, was surveyed. Joint results of a multiple regression analysis and path analysis supported the proposed model (CFI, GFI and NFI = .99, RMSEA < .06). Results indicate that when volunteer coordinators have a transformational style, volunteers have a higher intention to remain and that this relationship between transformational leadership style and intention to remain is partially mediated by satisfaction, organizational commitment, and role identity. The results seem to indicate that a useful strategy when running programs to increase the retention of volunteers is to train their coordinators in transformational leadership skills

La literatura sobre liderazgo ha proporcionado suficiente evidencia de que ciertos estilos de liderazgo incrementan la satisfacción, el compromiso y la permanencia de los empleados. Sin embargo hay pocos estudios sobre el efecto de los estilos de liderazgo en los voluntarios. El presente estudio tiene como objetivo investigar la posible influencia del liderazgo transformacional en la permanencia del voluntariado. Nuestra primera hipótesis es que un estilo de liderazgo transformacional del coordinador de voluntariado incrementa la intención de permanencia. Nuestra segunda hipóteis es que esta relación está mediada por las variables del modelo de las tres fases del voluntariado (satisfacción, compromiso organizacional e identidad de rol). Para poner a prueba estas hipótesis se encuestó a una muestra de 417 voluntarios (73% mujeres), de 17 organizaciones sin fines de lucro, con una media de edad de 44 años. Los resultados conjuntos del análisis de regresión múltiple y del path análisis respaldaron el modelo propuesto (CFI, GFI y NFI = .99, RMSEA < .06). Los resultados indican que los voluntarios que tienen coordinadores de voluntariado que aplican un estilo transformacional tienen mayor intención de permanencia y que esta relación entre estilo de liderazgo transformacional e intención de permanencia está parcialmente mediada por la satisfacción, el compromiso organizacional y la identidad. Los resultados parecen indicar que una estrategía útil de la gestión de programas para aumentar la permanencia de los voluntarios es entrenar a sus coordinadores en habilidades relacionadas con el liderazgo tranformacional

La Psicología ante la Pandemia de la COVID-19 en España. La Respuesta de la Organización Colegial / No disponible

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Use of eltrombopag for patients 65 years old or older with immune thrombocytopenia.

BACKGROUND: Eltrombopag is useful for immune thrombocytopenia (ITP). However, results of clinical trials may not accurately mirror clinical practice reality. Here we evaluated eltrombopag for primary and secondary ITP in our ≥65-year-old population. METHODS: A total of 106 primary ITP patients (16 with newly diagnosed ITP, 16 with persistent ITP, and 74 with chronic ITP) and 39 secondary ITP patients (20 with ITP secondary to immune disorders, 7 with ITP secondary to infectious diseases, and 12 with ITP secondary to lymphoproliferative disorders [LPD]) were retrospectively evaluated. RESULTS: Median age of our cohort was 76 (interquartile range, IQR, 70-81) years. 75.9% of patients yielded a platelet response including 66.2% complete responders. Median time to platelet response was 14 (IQR, 8-21) days. Median time on response was 320 (IQR, 147-526) days. Sixty-three adverse events (AEs), mainly grade 1-2, occurred. The most common were hepatobiliary laboratory abnormalities (HBLAs) and headaches. One transient ischemic attack in a newly diagnosed ITP and two self-limited pulmonary embolisms in secondary ITP were the only thrombotic events observed. CONCLUSION: Eltrombopag showed efficacy and safety in ITP patients aged ≥65 years with primary and secondary ITP. However, efficacy results in LPD-ITP were poor. A relatively high number of deaths were observed.

Pattern of blood concentrations of 47 elements in two populations from the same geographical area but with different geological origin and lifestyles: Canary Islands (Spain) vs. Morocco.

The Canary Islands are one of the outermost regions of the European Union (EU), which are located barely 100 km from the coasts of Morocco. Although these islands are located in Africa, the degree of socioeconomic development and lifestyle in this archipelago is comparable to that of any other region of Europe. It is well established that the main determinants of human exposure to elements have to do both, with their place of residence and with habits related to their lifestyle. For this reason, we wanted to study the pattern of contamination by elements of these two populations so geographically close, but so different both in their lifestyle, and the geological origin of the territory where they live. Thus, we have determined the blood concentrations of 47 elements (including 25 rare earth elements (REE) and other minority elements (ME) widely employed in the hi-tech industry) in a paired sample of Moroccans (n = 124) and Canary Islands inhabitants (n = 120). We found that the levels of iron, selenium, zinc, arsenic, cadmium, strontium, and specially lead, were significantly higher in Moroccans than in Canarians, probably due to the intensive mining activity in this country. We also found significantly higher levels of the sum of REE and ME in Moroccans than in Canarians, possibly related to the inappropriate management of e-waste in this country. On the other hand, in the inhabitants of the Canary Islands we found higher levels of manganese, probably related to a higher degree of exposure to heavy traffic and exposure to Saharan dust of the people living in this region, and niobium and bismuth, probably related to the higher economic development in these islands. Our results indicate that the vicinity of both territories is not a major determinant of each other's contamination.

The Causes of School Failure in Secondary School Students: Validation of a Psychosocial Model with Structural Equations.

The objective of the study was to determine the causal effects of school failure (SF) among secondary school students, belonging to five public schools within the region of Girardota, Colombia, through the validation of a psychosocial model with structural equations. A total of 319 students, 25% more males, enrolled in classes between 6th and 11th year, with an average age of 14 years. Furthermore, 265 parents and 200 teachers were also included in the sample. Participants answered the questions raised in 9 instruments. Of the total number of students, 63.8% were surveyed. The instruments were subjected to a pilot test and to the judgment of experts. In order to reduce the amount of data, exploratory and confirmatory factorial analyses were used. Other techniques of multivariate analysis such as decision trees and linear regressions were also used in order to previously evaluate the relationships between the independent variables (IV) and the dependent variable (DV). Afterwards, the Full SEM was calculated, yielding a model consisting of 34 variables (10 latent and 24 observable), with the following indexes of goodness of fit: CMIN/DF = 1.146, p = .058, IFI = 0.974, TLI = .970, CFI = .974, RMSEA = .027 and PCLOSE = 0.998. Theoretically, the model confirms the predictive value of the selected variables, with respect to school failure. The results are applicable to both the design of educational policies and the direct intervention in the classroom. In both contexts, strategies can be developed that reduce factors that negatively affect school performance, actively linking students, teachers and parents.

Thrombopoietin receptor agonist switch in adult primary immune thrombocytopenia patients: A retrospective collaborative survey involving 4 Spanish centres.

OBJECTIVE: To describe the reasons for and result of thrombopoietin receptor agonists (TPO-RA) switching in adult immune thrombocytopenia (ITP) patients of 4 Spanish centres. METHODS: We retrospectively analysed all patients who received sequential treatment with both TPO-RA between 2010 and 2015 recording clinical and biological parameters. RESULTS: Twenty-six patients were included; 17 received first romiplostim and 9 received first eltrombopag. Reasons for switching were inefficacy (n = 10), patient preference (n = 8), side effects (n = 5) and excessive platelet count fluctuation (n = 3). When the switch was due to inefficacy, 100% of patients who received romiplostim first and 66% who received eltrombopag first responded to the second drug. It is significant that none of the patients who received romiplostim first reached the maximum recommended dose before switching. When the change was due to patient preference or because of side effects, 100% of the patients responded to both TPO-RA. Three patients changed from romiplostim to eltrombopag due to platelet count fluctuation; one did not respond and the fluctuation persisted in the remaining 2 patients. We also found 4 sustained remissions after administering the second TPO-RA, 2 of these with inefficacy of the first drug. CONCLUSION: TPO-RA switching is a feasible strategy in different scenarios with high probability of success.

Efficacy and safety of eltrombopag in persistent and newly diagnosed ITP in clinical practice.

Eltrombopag is safe and effective in primary chronic ITP. However, lack of clinical trials avoids a clear demonstration of its utility in newly diagnosed and persistent ITP. Our aim here is to report Spanish results for this type of patients. We retrospectively evaluated 220 adult primary ITP patients. According to standard definition, patients were allocated to newly diagnosed (n = 30), persistent (n = 30), and chronic (n = 160) ITP. Groups were homogenous regarding most relevant parameters. 180 (90%) of 220 patients achieved a platelet response (R) with 167 (75.9%) complete responses (CR) after a 15-month follow-up. No statistical significant differences among groups but a trend towards a greater efficacy in newly diagnosed ITP were observed (93.3% of responses with 86.7% of CR). Efficacy in persistent ITP (83.3% of responses with 80.0% of CR) and chronic ITP (79.4% of responses with 73.1% of CR) was similar. 70 patients (31.8%) experienced adverse events. 15 of them were grade 3-4. Most common adverse effects were headache and hepatobiliary laboratory abnormalities (HBLAs). One persistent ITP had a venous thrombosis and one chronic ITP had grade II myelofibrosis. We consider Eltrombopag use for the early stage ITP as effective and safe as it is in chronic ITP.

The causes of school failure in secondary school students: validation of a psychosocial model with structural equations

The objective of the study was to determine the causal effects of school failure (SF) among secondary school students, belonging to five public schools within the region of Girardota, Colombia, through the validation of a psychosocial model with structural equations. A total of 319 students, 25% more males, enrolled in classes between 6th and 11th year, with an average age of 14 years. Furthermore, 265 parents and 200 teachers were also included in the sample. Participants answered the questions raised in 9 instruments. Of the total number of students, 63.8% were surveyed. The instruments were subjected to a pilot test and to the judgment of experts. In order to reduce the amount of data, exploratory and confirmatory factorial analyses were used. Other techniques of multivariate analysis such as decision trees and linear regressions were also used in order to previously evaluate the relationships between the independent variables (IV) and the dependent variable (DV). Afterwards, the Full SEM was calculated, yielding a model consisting of 34 variables (10 latent and 24 observable), with the following indexes of goodness of fit: CMIN/DF = 1.146, p = .058, IFI = 0.974, TLI = .970, CFI = .974, RMSEA = .027 and PCLOSE = 0.998. Theoretically, the model confirms the predictive value of the selected variables, with respect to school failure. The results are applicable to both the design of educational policies and the direct intervention in the classroom. In both contexts, strategies can be developed that reduce factors that negatively affect school performance, actively linking students, teachers and parents (AU)

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Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia.

Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 10(9) /l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 10(9) /l (n = 29), patient's request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 (range, 6-25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP < 1 year. Eleven patients were male and their median age was 59 years. They received a median of 4 previous treatment lines and 42% were splenectomized. No predictive factors of sustained response after eltrombopag withdrawal were identified. Platelet response following eltrombopag cessation may be sustained in an important percentage of adult primary ITP patients who achieved CR with eltrombopag. However, reliable markers for predicting which patients will have this response are needed.

Use of eltrombopag after romiplostim in primary immune thrombocytopenia.

The thrombopoietin receptor agonists (THPO-RAs), romiplostim and eltrombopag, are effective and safe in immune thrombocytopenia (ITP). However, the value of their sequential use when no response is achieved or when adverse events occur with one THPO-RA has not been clearly established. Here we retrospectively evaluated 51 primary ITP adult patients treated with romiplostim followed by eltrombopag. The median age of our cohort was 49 (range, 18-83) years. There were 32 women and 19 men. The median duration of romiplostim use before switching to eltrombopag was 12 (interquartile range 5-21) months. The reasons for switching were: lack of efficacy (n = 25), patient preference (n = 16), platelet-count fluctuation (n = 6) and side-effects (n = 4). The response rate to eltrombopag was 80% (41/51), including 67% (n = 35) complete responses. After a median follow-up of 14 months, 31 patients maintained their response. Efficacy was maintained after switching in all patients in the patient preference, platelet-count fluctuation and side-effect groups. 33% of patients experienced one or more adverse events during treatment with eltrombopag. We consider the use of eltrombopag after romiplostim for treating ITP to be effective and safe. Response to eltrombopag was related to the cause of romiplostim discontinuation.

A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer.

In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.

To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).