Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

176. Viper envenomation with ocular neurotocic effects managed without antidote admiistration:a case report 39th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 21-24 May 2019, Naples, Italy

Along with the more common clinical features, European viper envenomations may rarely present with neurotoxic manifestations. Those include muscle weakness, drowsiness, paresthesia, dyspnea and ocular complaints among others. Ocular neurotoxicity as an indication for antidote administration is still debated In this case the management with supportive/symptomatic treatment was sufficient. CASE REPORT. In May 2018, a 19-­‐year old man was admitted to an external emergency unit 20 minutes after a viper bite on the proximal phalanges of the right hand. The Poison Control Centre (PCC) of Policlinico Umberto I Hospital – Sapienza University of Rome was contacted immediately. Local signs of envenomation with fang marks, and swelling of the hand were present. Initial lab work showed no abnormalities. In the following 2 hours edema extended to the middle forearm (Figure 1), and one episode of vomiting was registered. The patient was hydrated and analgesics administered. Four hours post-­‐bite, edema did not progress proximally, but weakness, vertigo and mild abdominal pain were reported. LeuKocytosis (17.0 × 109/L, 90% neutrophils) and increased creatinkinase (245 U/L) were present. The PCC provided two vials of Viper Venom Antitoxin (Biomed) with no indication to administer at this time, but to closely monitor patient for any systemic and neurological manifestations. Seven hours post-­ bite,the swelling was stable, abdominal pain and previous neurological symptomsm regressed, and left ptosis appeared. Laboratory exams showed persistence of leukocytosis (16.6 × 109/l), glucose 123 mg/dL and creatinkinase 216 U/L. The PCC recommended further monitoring. Eighteen hours post-­‐bite ptosis ameliorated, no systemic signs had developed. The patient was discharged 40 hours post-­‐bite with no ptosis, edema in regression and leucocytes towards normalization. This case report suggests the following observations: i) as previously reported, neurological manifestations due to neurotoxins in some viper species venom may be characterized by delayed onset (up to 24 hours, 4-­‐7 hours in this case), association with mild local effects and reversibility; ii) weakness and vertigo preceded the ocular signs, and resolved in about 3 hours; iii) symptomatic management and close monitoring might be the best approach in such cases, with antitoxin recommended as soon as rapid edema extension and/or severe systemic/neurological symptoms appear

An outbreak of foodborne botulism in Rome

Objective: Foodborne botulism is caused by consumption of preformed Clostridium botulinum toxins (BoNT) in food. Although rare events, botulism outbreaks, especially those involving commercially prepared products, represent a public health emergency, given the potential for a large number of cases [1]. Case series: In November 2016, a 71-year old male (Case 1) presented to Umberto I Emergency Department (ED) with a 5-day history of diplopia, xerostomia, and constipation. He was afebrile with normal vital signs. Neurological examination confirmed left and right diplopia in the lateral vision, with no deficit in muscles tone, coordination, and osteotendon reflexes. He was held for further tests; the symptoms did not resolve. The Poison Control Center was alerted 2 days later, and a detailed anamnesis and food history revealed a meal consumed 10 days earlier with four friends in a public eatery. One of them was already hospitalized elsewhere for head trauma following a sudden fall, and showed severe weight loss (Case 2). Botulism was considered and then strongly suspected when informed by the local health department of a confirmed case in a patient who ate at the same restaurant on the same day. The remaining three diners were evaluated in our ED shortly after. Two (Case 3 and 4) reported dysphagia, diplopia, and constipation, associated with ptosis in one case. One patient was asymptomatic and discharged. An industrial preparation of vegetables in oil, used as a sandwich filling, was considered the most likely source. Trivalent-Equine Antitoxin (750 IU-anti-A, 500 IU-anti-B, and 50 IU-anti-E per mL) was administered. There was no progression of clinical signs and no one required mechanical ventilation. BoNT-producing clostridia, identified as type B, were detected in fecal samples. Patients were discharged after 12 (Case 1), 19 (Case 2) and 23 days (Case 3 and 4), respectively. In total, the outbreak produced 5 confirmed cases. Conclusion: This report allows the follow considerations: (i) mildly symptomatic botulism cases may escape recognition; (ii) clinicians should be trained to consider a diagnosis of botulism: an initial suspicion may lead to identification of other cases originally misdiagnosed; (iii) collaboration of medical and public health professionals is key to link multiple suspected cases to a common exposure. In summary, secondary prevention, which includes rapid identification, epidemiologic linkages of cases, and control of outbreaks resulting from contaminated food, is beneficialto prevent further spread and reduce morbidity and costs

Probable case of botulism: treating with a grain of salt

Objective: Foodborne botulism is caused by ingestion of neurotoxins of Clostridium botulinum. Confirmed diagnosis is based on isolation of toxin in patient and/or food samples, but there are also cases with suggestive clinical symptoms associated with negative laboratory testing and responsive to specific antitoxin therapy. Case report: On December 2016, a 39-year-old woman was admitted in a clinical department of Policlinico Umberto I for diarrhea and dysarthria. Antibiotic and antiviral therapy was prescribed. Neurological exam was normal, and computerised tomography (CT) scan, magnetic resonance imaging (MRI), and cerebrospinal fluid analysis were negative. Three days later, symptoms progressed with the onset of ptosis, mydriasis, ophthalmoplegia, diplopia, xerostomia, dysphagia, and constipation, and the Poison Control Center was alerted. Foodborne botulism was suspected based on the anamnestic data, symptom onset and exclusion of other possible conditions. Rectal swabs were taken and Trivalent-Equine-Antitoxin (TEqA, 750 IU-anti-A, 500 IU-anti-B, 50 IU-anti-E per mL) was requested. Food samples consisting of inoil industrial preparations of meat and vegetables in spreadable paste (patè) consumed regularly by the patient were collected and sent for laboratory analysis. Antitoxin was then administered with a slow and progressive clinical amelioration over 48 hours. Culture of food samples revealed the presence of toxin producing Clostridium, while patient samples were negative. In the following days, ocular symptoms continued to improve, although a nasogastric tube was positioned for nutrition as liquid and solid dysphagia persisted. Fourteen days later, dysphagia for liquids and constipation resolved. Gradual improvement of symptoms continued over one month and she was discharged with a persistent diplopia. Two outpatient ophthalmological examinations at two and three months showed a gradual resolution of diplopia. On telephone follow-up, the patient reported facial muscles weakness four months after recovery. Conclusion: This case allows the following considerations: (i) given that bacterial isolation in food does not constitute a valid laboratory diagnostic criterion, presence of clinical and epidemiological criteria may define a probable botulism case [1]; (ii) neuromuscular sequelae several years after the critical phase have been reported [2], and may escape recognition if long-term follow-up sessions are not scheduled

Impact of the media on the Poison Control Centres: the false outbreak of Loxosceles Rufescens spider bite in Italy

Objective.To describe the increment of telephone calls to the Poison Control Centre (PCC) of Policlinico Umberto I Hospital – Sapienza University of Rome related to Loxosceles Rufescens (LR) spider bites following an alarming awareness campaign in the media. Methods.The telephone calls to the PCC on alleged LR bites from April 2016 to September 2018 were reviewed. The month of April 2018, when the lay press published the first alarming article, was identified as an index. Data were normalized for the increase in the overall consultations registered in 2018. Results.The recorded enquiries regarding LR bites were as follows: i) 22 calls over the two years period April 2016 - March 2018, of which 4 from Emergency Department (ED) and 18 from private citizens; ii) 79 calls from April 2018 to September 2018, of which 18 from ED and 61 from private citizens. The mean age of subjects was 49 years (range: 12 months - 86 years). Only 2 subjects presented a skin lesion suggestive of LR: i) a 3-year old child hospitalized for 1 day for a necrotic skin lesion and low-grade fever. ii) a 61-years old man who presented an ulcerative skin lesion and was already treated at home with oral antibiotic therapy.Conclusions.Irrational fears about insects and other arthropods are very common. LR rarely bites humans and, contrary to what often stated or claimed, its bite causes minor, transient effects. Currently, there is no known fatal case. The “lethal” reputation of LR is mostly predicated by the lay press. It is well-known that the increase in mass media coverage is associated with an increase in ED admissions.This report allows the follow considerations: i) the mass media play a pivotal role in public health behavior and may influence health care utilization, ii) medical news reports may cause alarm, often unjustified, and may have significant costs either in terms of public health or in terms of people’s quality of life, iii) diagnoses of LR bite are mostly incorrect or refer at least to non-verified bites

Sex differences in oncogenic mutational processes

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.Peer reviewe

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that -80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAFPeer reviewe