Screening of CNVs using NGS data improves mutation detection yield and decreases costs in genetic testing for hereditary cancer.

INTRODUCTION: Germline CNVs are important contributors to hereditary cancer. In genetic diagnostics, multiplex ligation-dependent probe amplification (MLPA) is commonly used to identify them. However, MLPA is time-consuming and expensive if applied to many genes, hence many routine laboratories test only a subset of genes of interest. METHODS AND RESULTS: We evaluated a next-generation sequencing (NGS)-based CNV detection tool (DECoN) as first-tier screening to decrease costs and turnaround time and expand CNV analysis to all genes of clinical interest in our diagnostics routine. We used DECoN in a retrospective cohort of 1860 patients where a limited number of genes were previously analysed by MLPA, and in a prospective cohort of 2041 patients, without MLPA analysis. In the retrospective cohort, 6 new CNVs were identified and confirmed by MLPA. In the prospective cohort, 19 CNVs were identified and confirmed by MLPA, 8 of these would have been lost in our previous MLPA-restricted detection strategy. Also, the number of genes tested by MLPA across all samples decreased by 93.0% in the prospective cohort. CONCLUSION: Including an in silico germline NGS CNV detection tool improved our genetic diagnostics strategy in hereditary cancer, both increasing the number of CNVs detected and reducing turnaround time and costs.

Targeted nanopore sequencing by real-time mapping of raw electrical signal with UNCALLED.

Conventional targeted sequencing methods eliminate many of the benefits of nanopore sequencing, such as the ability to accurately detect structural variants or epigenetic modifications. The ReadUntil method allows nanopore devices to selectively eject reads from pores in real time, which could enable purely computational targeted sequencing. However, this requires rapid identification of on-target reads while most mapping methods require computationally intensive basecalling. We present UNCALLED ( https://github.com/skovaka/UNCALLED ), an open source mapper that rapidly matches streaming of nanopore current signals to a reference sequence. UNCALLED probabilistically considers k-mers that could be represented by the signal and then prunes the candidates based on the reference encoded within a Ferragina-Manzini index. We used UNCALLED to deplete sequencing of known bacterial genomes within a metagenomics community, enriching the remaining species 4.46-fold. UNCALLED also enriched 148 human genes associated with hereditary cancers to 29.6× coverage using one MinION flowcell, enabling accurate detection of single-nucleotide polymorphisms, insertions and deletions, structural variants and methylation in these genes.

Impact of migrancy on cancer clinical trial participation: Factors associated with approach and consent in Australian-born versus migrant groups.

BACKGROUND/AIMS: This study compared rates of clinical trial participation and perceived adequacy of information provided prior to consent in migrant and Australian-born cancer patients, and explored factors associated with being approached and agreeing to participate. METHODS: We utilized data from a larger cross-sectional survey assessing disparities in patient-reported outcomes in Chinese, Arabic, or Greek migrant versus English-speaking Australian-born cancer patients. Participants completed a questionnaire eliciting demographic and disease details, communication challenges, whether invited and consented to a clinical trial, and if so, adequacy of information received. RESULTS: A total of 566 migrants (142 Arabic, 251 Chinese, and 173 Greek) and 270 English-speaking Australian-born patients participated. Overall, 25% were approached to participate in clinical trials, and of these, 74% consented. Migrants were significantly less likely to consent if asked to participate in clinical trials (P = .009), and fewer migrants (67.2%) reported receiving sufficient information prior to deciding on trial participation (82.1%; P = .04). Perceived understanding of the health system (odds ratio [OR] = 0.71), confidence in speaking (OR = 0.75), ability to understand English (OR = 0.80), and communicate with doctors in English (OR = 0.81) were significantly related to patients' likelihood of being approached to participate in clinical trials. Perceived understanding of the health system (OR = 0.66) was significantly associated with patients agreeing to take part in cancer clinical trials. CONCLUSIONS: Our findings identified that barriers to migrants' self-reported participation in clinical trials include perceived lack of understanding of the health system and low English proficiency. Strategies that address these barriers are needed to increase migrant patients' participation in cancer clinical trials.

Open questions: why are babies rarely born with cancer?

Childhood cancer is fundamentally a disease of dysregulated development. Why does it rarely occur during the fetal period, a time of enormous growth and development?

Neonatal solid tumors.

BACKGROUND: Neonatal tumors are different from tumors of the older children and knowledge gained from treating older children can not be extrapolated to neonates. Neonates have immature physiology and their haematopoietic and immune systems are not fully developed and the response to therapy is unpredictable. Hence it is imperative to study these tumors as separate entity. The aim of this study is to analyse this rare set of tumors in terms of their incidence, clinical features and management. MATERIALS AND METHODS: All babies admitted in our hospital with tumors from January, 2011 to January 2016 were studied. Tumor-like conditions like haemangioma, lymphangioma and hamartomas were included. The age, sex distribution, type of tumor and management were studied. RESULTS: A total of 51 cases were registered out of which, 29 cases were haemangiomas and lymphangiomas. Of remaining 20 cases, 5 were benign ovarian cysts, 3 were neuroblastomas, 3 were congenital fibrosarcomas, 3 were sacrococcygeal teratomas. Wilm's tumor, congenital mesoblastic nephroma, haemangioendothelioma of liver and others formed the remaining six cases. CONCLUSION: Our study insists that the neonatal tumors are distinct subset of pediatric tumors, requiring careful selection of treatment modalities and most of the solid tumors can be successfully managed if diagnosed and treated early. Neonatal tumors are defined as tumors which are diagnosed before the first month of life. Some of them can be congenital (present at birth). Neonatal tumors are different from tumors in older children in terms of etiopathogenesis, behavior and response to therapy as well as long-term outcomes.

Papilomatosis laríngea juvenil y su relación con la infección genital por virus de papiloma humano durante el embarazo / Laryngeal papillomatosis youth and their relationship with infection Genital human papilloma virus during pregnancy

OBJETIVO: establecer la relación entre el diagnóstico de papilomatosis laríngea juvenil y la infección genital por virus de papiloma humano durante el embarazo. MÉTODOS: Se incluyeron 18 madres de hijos con diagnóstico de papilomatosis laríngea juvenil. Se revisaron las historias de los niños, se realizó anamnesis a las madres buscando antecedentes de infección por virus de papiloma humano durante el embarazo, se practicó evaluación ginecológica actual, citología, vulvoscopia, vaginoscopia, colposcopia y biopsia, de ser necesario. Se tomaron muestras para tipificación viral. RESULTADOS: Hubo 120 casos de papilomatosis laríngea juvenil entre 14 400 pacientes, para una frecuencia de 0,8 %. Entre los pacientes evaluados, predominó el sexo masculino (61,1 %). La edad al momento del diagnóstico fue de 5,7 ± 3,2 años. La enfermedad tenía una mediana de evolución de 2 años. La mediana del número de intervenciones quirúrgicas requeridas por paciente, fue 3. Las manifestaciones clínicas más frecuentes fueron disnea (83,3 %), y disfonía (61,1 %). El genotipo viral en las lesiones laríngeas fue 6 (50 %), 11 (11,1 %) y coinfección 6 y 11 (11,1 %). Se detectó virus de papiloma humano en 5 madres: 3 de alto riesgo y 2 no tipificables. La vía del parto vaginal fue la más frecuente con un 83,3 %. CONCLUSIONES: La papilomatosis laríngea es poco frecuente (0,8 %), genera un cuadro de severidad variable caracterizado por disnea y disfonía, es producido por papilomavirus humano 6 y 11 y se asocia al nacimiento vía vaginal. No hubo correlación entre los tipos virales de madres e hijos.

OBJECTIVE: to establish the relationship between the diagnosis of juvenile laryngeal papillomatosis and genital infection with human papilloma virus during pregnancy. METHODS: 18 mothers whose children’s diagnoses were juvenile laryngeal papillomatosis were included. The children’s history were checked, the mothers were given the anamnesis procedure looking for human papilloma virus infections during pregnancy, they were given actual gynecologic evaluations, citology, vulvoscopy, vaginoscopy, colposcopy and biopsy where needed. Samples were taken for their viral tipification. RESULTS: There were 120 cases of juvenile laryngeal papillomatosis in 14400 patients, an 0.8% frecuency. Amongst the evaluated patients, most were males (61.1 %). Age at diagnosis was 5.7 ± 3.2 años. The disease had an evolution median time of 2 years. The medical intervention median per patient was 3. The most frecuent clinical manifestations were disnea (83.3 %) and dysphonia (61.1%). The viral genotype on laryngeal lesions was 6 (50%), 11 (11.11 %) and coinfection 6 y 11 (11.1 %). Human papilloma virus was detected in 5 mothers: 3 high risk and 2 non classifiable. Vaginal birth was the most frequent with an 83.3 % rate. CONCLUSION: Juvenile laryngeal papillomatosis is not very frequent (0.8 %), generates a manifestation of variable severity characterized by dysnea and dysphonia, produced by human papillomavirus 6 and 11 and is associated to vaginal birth. There was no correlation between the viral types of mothers and children.

[Radiological evaluation of congenital tumors]. / Radiografía del abdomen en Urgencias. ¿Una exploración para el recuerdo?

In this article, we consider tumors that are diagnosed during pregnancy or in the first three months of life. This is a heterogeneous group of neoplasms with special biological and epidemiological characteristics that differentiate them from tumors arising in children or adults. In the last two decades, the prenatal detection of congenital tumors has increased due to the generalized use of prenatal sonographic screening. Advances in imaging techniques, especially in fetal magnetic resonance imaging, have enabled improvements in the diagnosis, follow-up, clinical management, and perinatal treatment of these tumors. This image-based review of the most common congenital tumors describes their histologic types, locations, and characteristics on the different imaging techniques used.

[Diagnosis and management of lung cancer during pregnancy]. / Le cancer bronchique de la femme enceinte : prise en charge diagnostique et thérapeutique en 2012.

The incidence of lung cancer during pregnancy is very low, but it is becoming more frequent in industrialized countries both because of the increase in smoking in young women and because women are becoming pregnant later in life. Usually, the cancer has a poor prognosis due to the presence of metastatic disease at the time of diagnosis. Diagnosis and management are delicate, and should deal with the gestational age, the maternal prognosis, the fetal toxicity of treatments, but also with the worsening of maternal prognosis and the risk of neoplastic cells being transmitted to the fetus in case of delayed treatment. Psychological and ethical considerations complicate the decision process. We present a review of the epidemiology, clinical characteristics, management, and prognosis concerning lung cancer during pregnancy. Finally, it is important to remember that young women with lung cancer should be advised to use a reliable form of contraception.

Los teratomas, verdaderos monstruos en la infancia: caso clínico de un teratoma maduro ováricos / Teratomas, real monsters in childhood: Case report of a mature ovarian teratoma

Los Teratoma son tumores que contienen más de dos capas germinales del embrión, de localización variable, frecuentes en la infancia, benignos en su mayoría, con una base genética en estudio, cuyo tratamiento y pronostico va a depender de múltiples factores dentro de los que destaca su com - portamiento histológico...(AU)

Tumor disease and associated congenital abnormalities on prenatal MRI.

OBJECTIVE: Fetal tumors can have a devastating effect on the fetus, and may occur in association with congenital malformations. In view of the increasing role of fetal magnetic resonance imaging (MRI) as an adjunct to prenatal ultrasonography (US), we sought to demonstrate the visualization of fetal tumors, with regard to congenital abnormalities, on MRI. MATERIALS AND METHODS: This retrospective study included 18 fetuses with tumors depicted on fetal MRI after suspicious US findings. An MRI standard protocol was used to diagnose tumors judged as benign or malignant. All organ systems were assessed for tumor-related complications and other congenital malformations. Available US results and histopathology were compared with MRI. RESULTS: There were 13/18 (72.2%) benign and 5/18 (27.8%) malignant tumors diagnosed: a cerebral primitive neuroectodermal tumor in 1/18, head-neck teratomas in 4/18; ventricular rhabdomyomas in 4/18; a cardiac teratoma in 1/18; a hepatoblastoma in 1/18; neuroblastomas in 2/18; a cystic hemorrhagic adrenal hyperplasia in 1/18; a pelvic leiomyoma in 1/18; sacrococcygeal teratomas in 3/18. Tumor-related complications were present in 13/18 (72.2%) cases; other congenital abnormalities in 3/18 (16.7%). MRI diagnosis and histology were concordant in 8/11 (72.7%) cases. In 6/12 (50%) cases, US and MRI diagnoses were concordant, and, in 6/12 (50%) cases, additional MRI findings changed the US diagnosis. CONCLUSION: Our MRI results demonstrate the visualization of fetal tumors, with frequently encountered tumor-related complications, and other exceptional congenital abnormalities, which may provide important information for perinatal management. Compared to prenatal US, MRI may add important findings in certain cases.

Inflammation and oncogenesis: a vicious connection.

Epidemiological and experimental data suggest a close connection between inflammation and tumorigenesis. Solid tumors are typically infiltrated with immune cells and inflammation impacts most, if not all, stages of tumorigenesis. Molecular and cellular pathways, which connect inflammation and cancer, have emerged as attractive targets for prevention and therapy. In this review we discuss general mechanisms and concepts of cancer promoting inflammation.

Approaches to the management of antenatally diagnosed congenital tumours.

Congenital fetal tumours are rare, but current imaging modalities including US and MRI facilitate antenatal diagnosis and investigation, allowing a presumptive diagnosis and management strategy. Although the prevalence of fetal tumours is difficult to ascertain, an incidence of 7.2 per 100,000 live births has previously been reported, with the incidence of neonatal malignancy estimated at 36.5 per million births. Teratomas and neuroblastomas are the most common solid tumours described. Tumours may be very large or associated with severe hydrops leading to significant dystocia with the potential for difficult vaginal or caesarean delivery. Once the diagnosis of a fetal tumour is made, optimal management incorporates a multidisciplinary approach including obstetrician, neonatologist, paediatric surgeon and paediatric oncologist so that counselling is appropriate and a clear management plan is in place for parents.

Tumours of the fetal body: a review.

Tumours of the fetal body are rare, but lesions have been reported in all spaces, especially in the mediastinum, the pericardial space, the adrenals, the kidney, and the liver. Lymphangioma and teratoma are the commonest histological types encountered, followed by cardiac rhabdomyoma. Adrenal neuroblastoma is the commonest malignant tumour. Imaging plays an essential role in the detection and work-up of these tumours. In addition to assisting clinicians it also helps in counselling parents. Most tumours are detected by antenatal US, but fetal MRI is increasingly used as it brings significant additional information in terms of tumour extent, composition and complications.

Benefits and burden of the maternally-mediated immunological imprinting.

The ontogenetic development of both the immune and the nervous system entirely depend on external environmental signals that induce a lifelong learning process. The resulting collective immunological knowledge about the external world is transmitted in an epi-genetic fashion to the offspring, but only from the maternal and not the paternal side, with maternal IgG as the main transgenerational vector. As products of thymus-dependent responses, maternal IgG have undergone immune maturation by somatic hypermutations and are, therefore, acquired immunological phenotypes representing a great deal of the mother's immunological experience. During a limited neonatal imprinting period, maternal antibodies induce T cell-dependent idiotypic responses. These exert up to life-long determinative influences which may even be dominant over seemingly genetic predispositions. Such long-term immunological imprinting effects can be detected as (a) selection of the adult T and B cell repertoires, (b) anti-microbial protection by antigen-reactive antibodies (idiotypes) and anti-idiotypes, (c) allergen-specific suppression of IgE responsiveness by allergen-reactive IgG idiotype or corresponding anti-idiotype and (d) induction of autoimmune diseases by maternally-derived autoantibodies. Hence, immunological imprinting by maternal IgG antibodies will mostly be beneficial, but in case of autoantibodies can also be a burden for the initial development of the nascent immune system.