The Complexity of Tobacco Smoke-Induced Mutagenesis in Head and Neck Cancer.

Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). Here, we further explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported. Differences in HNC incidence between countries corresponded with differences in mutation burdens of tobacco-associated signatures, consistent with the dominant role of tobacco in HNC causation. Differences were found in the burden of tobacco-associated signatures between anatomical subsites, suggesting that tissue-specific factors modulate mutagenesis. We identified an association between tobacco smoking and three additional alcohol-related signatures indicating synergism between the two exposures. Tobacco smoking was associated with differences in the mutational spectra and repertoire of driver mutations in cancer genes, and in patterns of copy number change. Together, the results demonstrate the multiple pathways by which tobacco smoke can influence the evolution of cancer cell clones.

Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor.

Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues.

Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.

Implementation of dietary and general lifestyle advice among women with polycystic ovarian syndrome.

AIMS: Central obesity and insulin resistance are strongly implicated in the etiology of polycystic ovarian syndrome (PCOS) and their reduction is therefore a central treatment focus. Weight loss has been consistently successful in reducing insulin resistance and restoring ovulation and fertility in women with PCOS. The purpose of the current study is to investigate the general attitudes towards dieting and exercise in women with PCOS, together with the extent of implementation of the dietary and lifestyle advice that these women are given as part of their treatment. General knowledge of patients about their condition (PCOS) has also been assessed. METHODS: Fifty three pre-menopausal women, over the age of 18 years, with a confirmed diagnosis of PCOS, were recruited from the Endocrinology Department, Middlesex Hospital, London. Subjects were interviewed individually using an interview-guided questionnaire. RESULTS: Sixty four per cent of the subjects were overweight (BMI > 25 kg/m2) and 55% of those were obese (BMI > 30 kg/m2). All subjects identified the importance of weight control in the management of their condition. However, only nine out of the 35 overweight women had actually been referred to a dietician and only 22 reported taking moderate exercise at least once a week in order to improve their health. The main sources of information on weight management were the internet and their consultant endocrinologist, who they normally see only twice a year. CONCLUSION: In spite of the fact that weight loss and weight maintenance are absolutely vital in the treatment of PCOS, our study has shown that the support given to PCOS patients to help reduce and control their weight is inadequate and needs to be improved.

The long-term cost-effectiveness of the use of Functional Electrical Stimulation for the correction of dropped foot due to upper motor neuron lesion.

OBJECTIVE: Functional Electrical Stimulation (FES) for correction of dropped foot has been shown to increase mobility, reduce the incidence of falls and to improve quality of life. This study aimed to determine how long the intervention is of benefit, and the total cost of its provision. DESIGN: Retrospective review of medical records. PARTICIPANTS: One hundred and twenty-six people with spastic dropped foot (62 stroke, 39 multiple sclerosis, 7 spinal cord injury, 3 cerebral palsy, 15 others) who began treatment in the year 1999. METHOD: All received common peroneal nerve stimulation, producing dorsiflexion and eversion time to the swing phase of gait using a heel switch. Device usage, 10 m walking speed and Functional Walking Category (FWC) were recorded. RESULTS: The median time of FES use was 3.6 years (mean 4.9, standard deviation 4.1, 95% confidence interval 4.2-5.6) with 33 people still using FES after a mean of 11.1 years. People with stroke walked a mean of 45% faster overall, including a 24% training effect with 52% improving their FWC. People with multiple sclerosis did not receive a consistent training effect but walked 29% faster when FES was used with 40% increasing their FWC. The average treatment cost was £3,095 per patient resulting in a mean cost per Quality Adjusted Life Years of £15,406. CONCLUSION: FES is a practical, long-term and cost-effective treatment for correction of dropped foot.