Genome-wide association study of esophageal squamous cell cancer identifies shared and distinct risk variants in African and Chinese populations.

Esophageal squamous cell carcinoma (ESCC) has a high disease burden in sub-Saharan Africa and has a very poor prognosis. Genome-wide association studies (GWASs) of ESCC in predominantly East Asian populations indicate a substantial genetic contribution to its etiology, but no genome-wide studies have been done in populations of African ancestry. Here, we report a GWAS in 1,686 African individuals with ESCC and 3,217 population-matched control individuals to investigate its genetic etiology. We identified a genome-wide-significant risk locus on chromosome 9 upstream of FAM120A (rs12379660, p = 4.58 × 10-8, odds ratio = 1.28, 95% confidence interval = 1.22-1.34), as well as a potential African-specific risk locus on chromosome 2 (rs142741123, p = 5.49 × 10-8) within MYO1B. FAM120A is a component of oxidative stress-induced survival signals, and the associated variants at the FAM120A locus co-localized with highly significant cis-eQTLs in FAM120AOS in both esophageal mucosa and esophageal muscularis tissue. A trans-ethnic meta-analysis was then performed with the African ESCC study and a Chinese ESCC study in a combined total of 3,699 ESCC-affected individuals and 5,918 control individuals, which identified three genome-wide-significant loci on chromosome 9 at FAM120A (rs12379660, pmeta = 9.36 × 10-10), chromosome 10 at PLCE1 (rs7099485, pmeta = 1.48 × 10-8), and chromosome 22 at CHEK2 (rs1033667, pmeta = 1.47 × 10-9). This indicates the existence of both shared and distinct genetic risk loci for ESCC in African and Asian populations. Our GWAS of ESCC conducted in a population of African ancestry indicates a substantial genetic contribution to ESCC risk in Africa.

Usefulness of high-risk HPV early oncoprotein (E6 and E7) serological markers in the detection of cervical cancer: A systematic review and meta-analysis.

We reviewed the literature on the importance of selected anti-high-risk human papillomavirus (HR-HPV) antibodies (namely, 16/18 and early oncoproteins E6 and E7) as potential serological markers for early detection of individuals at high risk of cervical cancer. We searched for studies in PubMed and Embase databases published from 2010 to 2020 on antibodies against HR-HPV E6 and E7 early proteins and cervical cancer. Pooled sensitivity and specificity for HPV16 and HPV18 antibodies were calculated using a bivariate hierarchical random-effects model. A total of 69 articles were identified; we included three studies with 1550 participants. For the three HPV16/18 E6 and E7 antibody tests, enzyme-linked immunosorbent assay-based assays had a sensitivity of 18% for detecting CIN2+ (95% confidence interval [CI]: 15-21) and a specificity of 96% (95% CI: 92-98), for slot-blot, sensitivity was 28.9% (95% CI: 23.3-35.1) and specificity was 72% (95% CI: 66.6-77.0) for detecting CIN2+, and for multiplex HPV serology assay based on a glutathione S-transferase, sensitivity was 16% (95% CI: 8.45-28.6) and specificity was 98% (95% CI: 97-99) for detecting invasive cervical cancer. HR-HPV16/18 E6 and E7 serological markers showed high specificity, but sensitivity was suboptimal for the detection of cervical cancer in either population screening settings or as point-of-care screening tests.

Towards implementation of comprehensive breast cancer risk prediction tools in health care for personalised prevention.

Advances in knowledge about breast cancer risk factors have led to the development of more comprehensive risk models. These integrate information on a variety of risk factors such as lifestyle, genetics, family history, and breast density. These risk models have the potential to deliver more personalised breast cancer prevention. This is through improving accuracy of risk estimates, enabling more effective targeting of preventive options and creating novel prevention pathways through enabling risk estimation in a wider variety of populations than currently possible. The systematic use of risk tools as part of population screening programmes is one such example. A clear understanding of how such tools can contribute to the goal of personalised prevention can aid in understanding and addressing barriers to implementation. In this paper we describe how emerging models, and their associated tools can contribute to the goal of personalised healthcare for breast cancer through health promotion, early disease detection (screening) and improved management of women at higher risk of disease. We outline how addressing specific challenges on the level of communication, evidence, evaluation, regulation, and acceptance, can facilitate implementation and uptake.

Understanding polygenic models, their development and the potential application of polygenic scores in healthcare.

The use of genomic information to better understand and prevent common complex diseases has been an ongoing goal of genetic research. Over the past few years, research in this area has proliferated with several proposed methods of generating polygenic scores. This has been driven by the availability of larger data sets, primarily from genome-wide association studies and concomitant developments in statistical methodologies. Here we provide an overview of the methodological aspects of polygenic model construction. In addition, we consider the state of the field and implications for potential applications of polygenic scores for risk estimation within healthcare.

Association of genetic variants in CHEK2 with oesophageal squamous cell carcinoma in the South African Black population.

Oesophageal squamous cell carcinoma (OSCC) has a high incidence in southern Africa and a poor prognosis. Limited information is available on the contribution of genetic variants in susceptibility to OSCC in this region. However, recent genome-wide association studies have identified multiple susceptibility loci in Asian and European populations. In this study, we investigated genetic variants from seven OSCC risk loci identified in non-African populations for association with OSCC in the South African Black population. We performed association studies in a total of 1471 cases and 1791 controls from two study sample groups, which included 591 cases and 852 controls from the Western Cape and 880 cases and 939 controls from the Johannesburg region in the Gauteng province. Thereafter, we performed a meta-analysis for 11 variants which had been genotyped in both studies. A single nucleotide polymorphism in the CHEK2 gene, rs1033667, was significantly associated with OSCC [P = 0.002; odds ratio (OR) = 1.176; 95% confidence interval (CI): 1.06-1.30]. However, single nucleotide polymorphisms in the CASP8/ALS2CR12, TMEM173, PLCE1, ALDH2, ATP1B2/TP53 and RUNX1 loci were not associated with the disease (P > 0.05). The lack of association of six of these loci with OSCC in South African populations may reflect different genetic risk factors in non-African and African populations or differences in the genetic architecture of African genomes. The association at CHEK2, a gene with key roles in cell cycle regulation and DNA repair, in an African population provides further support for the contribution of common genetic variants at this locus to the risk of oesophageal cancer.

pedigreejs: a web-based graphical pedigree editor.

Motivation: The collection, management and visualization of clinical pedigree (family history) data is a core activity in clinical genetics centres. However, clinical pedigree datasets can be difficult to manage, as they are time consuming to capture, and can be difficult to build, manipulate and visualize graphically. Several standalone graphical pedigree editors and drawing applications exist but there are no freely available lightweight graphical pedigree editors that can be easily configured and incorporated into web applications. Results: We developed 'pedigreejs', an interactive graphical pedigree editor written in JavaScript, which uses standard pedigree nomenclature. Pedigreejs provides an easily configurable, extensible and lightweight pedigree editor. It makes use of an open-source Javascript library to define a hierarchical layout and to produce images in scalable vector graphics (SVG) format that can be viewed and edited in web browsers. Availability and implementation: The software is freely available under GPL licence (https://ccge-boadicea.github.io/pedigreejs/). Contact: tjc29@cam.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors.

PURPOSE: Breast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs). METHODS: BOADICEA incorporates the effects of truncating variants in BRCA1, BRCA2, PALB2, CHEK2, and ATM; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information. RESULTS: Among all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with 14.7% of women predicted to have a lifetime risk of ≥17-<30% (moderate risk according to National Institute for Health and Care Excellence [NICE] guidelines) and 1.1% a lifetime risk of ≥30% (high risk). CONCLUSION: This comprehensive model should enable high levels of BC risk stratification in the general population and women with family history, and facilitate individualized, informed decision-making on prevention therapies and screening.

Liver cancer mortality trends in South Africa: 1999-2015.

BACKGROUND: In South Africa (SA), liver cancer (LC) is a public health problem and information is limited. METHODS: Joinpoint regression analysis was computed for the most recent LC mortality data from Statistics South Africa (StatsSA), by age group, sex and population group. The mortality-to-incidence ratios (MIRs) were calculated as the age-adjusted mortality rate divided by the age-adjusted incidence rate. RESULTS: From 1999 to 2015, the overall LC mortality significantly decreased in men (- 4.9%) and women (- 2.7%). Overall a significant decrease was noted in black African men aged 20-29 and 40-49 years, and white women older than 60 years but mortality rates increased among 50-59 and 60-69 year old black African men (from 2010/2009-2015) and women (from 2004/2009-2015). The mortality rates increased with age, and were higher among blacks Africans compared to whites in all age groups - with a peak black African-to-white mortality rate ratio of six in men and three in women at ages 30-39 years. The average MIR for black African men and women was 4 and 3.3 respectively, and 2.2 and 1.8 in their white counterparts. Moreover, decreasing LC mortality rates among younger and the increase in rates in older black Africans suggest that the nadir of the disease may be near or may have passed. CONCLUSIONS: Findings of population-age subgroup variations in LC mortality and the number of underdiagnosed cases can inform surveillance efforts, while more extensive investigations of the aetiological risk factors are needed. IMPACT: There was a large race, sex and age differences in trends of LC mortality in SA. These findings should inform more extensive evaluation of the aetiology and risk factors of LC in the country in order to guide control efforts.

How can we address the uncertainties regarding the potential clinical utility of polygenic score-based tests?

As common low penetrance variants associated with diseases are uncovered, attempts continue to be made to harness this knowledge for improving healthcare. Polygenic scores have been developed as the mechanism by which knowledge of common variants can be used to investigate genetic contributions to disease risk. They serve as a biomarker to provide an estimate of the genetic liability for a particular disease. Discussion continues as to whether polygenic scores are a useful biomarker and their readiness for incorporation into clinical and public health practice. In this paper, we investigate the key challenges that need to be addressed, in the description and assessment of the clinical utility of polygenic score-based tests for use in clinical and public health practice.

The risk of developing many common diseases, such as heart disease is influenced by both genetic and lifestyle factors. Polygenic scores (PGS) are one way of assessing an individual's risk of developing certain diseases. There is still uncertainty as to whether and how to use PGS for individual care. Much of this is because it is unclear as to whether tests that give a PGS can provide useful information for the care of individuals and patients as part of prevention or healthcare pathways. In this paper, we describe some of the challenges that need to be addressed, so that we can move forward and better understand when and how to use these tests for population and individual benefit.

CanRisk Tool-A Web Interface for the Prediction of Breast and Ovarian Cancer Risk and the Likelihood of Carrying Genetic Pathogenic Variants.

BACKGROUND: The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) state-of-the-art risk model and a forthcoming ovarian cancer risk model. METHODS: The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation. RESULTS: This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations. CONCLUSIONS: The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking. IMPACT: There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.

Evaluating clinician acceptability of the prototype CanRisk tool for predicting risk of breast and ovarian cancer: A multi-methods study.

BACKGROUND: There is a growing focus on the development of multi-factorial cancer risk prediction algorithms alongside tools that operationalise them for clinical use. BOADICEA is a breast and ovarian cancer risk prediction model incorporating genetic and other risk factors. A new user-friendly Web-based tool (CanRisk.org) has been developed to apply BOADICEA. This study aimed to explore the acceptability of the prototype CanRisk tool among two healthcare professional groups to inform further development, evaluation and implementation. METHOD: A multi-methods approach was used. Clinicians from primary care and specialist genetics clinics in England, France and Germany were invited to use the CanRisk prototype with two test cases (either face-to-face with a simulated patient or via a written vignette). Their views about the tool were examined via a semi-structured interview or equivalent open-ended questionnaire. Qualitative data were subjected to thematic analysis and organised around Sekhon's Theoretical Framework of Acceptability. RESULTS: Seventy-five clinicians participated, 21 from primary care and 54 from specialist genetics clinics. Participants were from England (n = 37), France (n = 23) and Germany (n = 15). The prototype CanRisk tool was generally acceptable to most participants due to its intuitive design. Primary care clinicians were concerned about the amount of time needed to complete, interpret and communicate risk information. Clinicians from both settings were apprehensive about the impact of the CanRisk tool on their consultations and lack of opportunities to interpret risk scores before sharing them with their patients. CONCLUSIONS: The findings highlight the challenges associated with developing a complex tool for use in different clinical settings; they also helped refine the tool. This prototype may not have been versatile enough for clinical use in both primary care and specialist genetics clinics where the needs of clinicians are different, emphasising the importance of understanding the clinical context when developing cancer risk assessment tools.

Johannesburg Cancer Study (JCS): contribution to knowledge and opportunities arising from 20 years of data collection in an African setting.

The Johannesburg Cancer Study (JCS) aims were to examine whether cancer risk factors identified in Western countries applied to black patients in Johannesburg, South Africa and to understand the impact of HIV on cancer risk, with a view to identifying previously unrecognised HIV associated cancers. A total of 24 971 black patients with an incident histologically proven (>95%) cancer of any type were enrolled between 1995-2016. Response rates were >90%. Patients provided informed consent, lifestyle and demographic information using a structured questionnaire; 19 351 provided a serum sample and 18 972 a whole blood sample for genomic analyses. This is currently the largest cancer epidemiological biobank in Africa. JCS uses a cancer case-control method; controls being cancer types unrelated to exposures of interest. Published results show the importance of HIV in several cancers known to be infection associated e.g. Kaposi sarcoma (OR = 1683; CI = 595-5194) in those with high Kaposi-sarcoma-associated-herpesvirus titres; no effect of HIV on lung or liver cancer-in the latter showing a strong association with HBVDNA, sAg and c positivity (OR = 47; CI = 21-104). Comparable data to higher-income country studies include lung cancer ORs in relation to smoking (15+g tobacco/day) (ORMales = 37; CI = 21-67, ORFemales = 18.5; CI = 8-45) and associations between alcohol and oesophageal cancer in smokers (ORM&F = 4.4; CI = 3-6). Relationship between hormonal contraception declined to null 10 or more years after stopping for breast (OR = 1.1; CI = 0.9-1.4) and cervical cancer (OR = 1.0;CI = 0.8-1.2), and protective effects shown, five or more years after stopping for ovarian (OR = 0.6; CI = 0.4-1) and endometrial cancer (OR = 0.4; CI = 0.2-0.9). Preferential access is based on data requests promoting data pooling, equal collaborative opportunities and enhancement of research capacity in South Africa. The JCS is a practical and valid design in otherwise logistically difficult settings.

Analysis of risk factors associated with hepatocellular carcinoma in black South Africans: 2000-2012.

OBJECTIVE: The aims of this study were to determine the prevalence of risk factors associated with hepatocellular carcinoma (HCC) in black adult South Africans and to estimate the size of the associated risks. METHODS: A case-control analysis of 150 black South African patients (aged 18-75 years) with HCC-who were a subset of patients recruited for the Johannesburg Cancer Case Control Study 2000 to 2012-was undertaken. The association between this tumour and hepatitis B/C virus infections, and human immunodeficiency virus (HIV) mono- and co-infections was investigated. Odds ratios (ORs) and 95% confidence intervals (CI) adjusted for age, year of diagnosis, marital status, place of birth and selected modifiable risk factors were calculated. RESULTS: HCC was significantly associated with a rural birthplace (p<0.05), being male and living in an urban area for 14 years or less. The Odds Ratio (OR) for HCC increased significantly with HBV DNA+/HBsAg+ (OR 34.5; CI:16.26-73.13), HBV DNA+/HBsAg- (OR 3.76; CI:1.79-7.92), HBV DNA level >2000 IU/ml (OR 8.55; CI:3.00-24.54) to ≥200,000 (OR 16.93; CI:8.65-33.13), anti-HCV (OR 8.98; CI:3.59-22.46), HBV DNA+/HIV+ co-infection (OR 5.36; CI:2.59-11.11), but not with HBV DNA-/HIV+ (OR 0.34; CI:0.14-0.85). We did not find a synergistic interaction between HBV and HIV. Modifiable risk factors (alcohol consumption, tobacco smoking, number of sexual partners, diabetes and hormonal contraceptive use) were nonsignificant. DISCUSSION: A considerable portion of the HCC burden in Johannesburg and surrounding provinces falls on rural migrants to urban areas, most of whom are men. The HBV will continue to contribute to HCC incidence in older age-groups and in others who missed vaccination. Although we did not find an increased risk for HCC in HIV positive individuals this may change as life expectancy increases due to greater access to antiretroviral therapies, necessitating the addition of hepatitis virus screening to preventive medical care.

The Integrity and Yield of Genomic DNA Isolated from Whole Blood Following Long-Term Storage at -30°C.

Long-term storage of whole blood can affect the integrity of DNA if it is not done under optimal conditions. The aim of this study was to determine whether long-term storage (2-19 years) of whole blood samples at -30°C had a negative effect on the quality or quantity of genomic DNA that could be recovered at extraction. Genomic DNA was isolated from 2758 whole blood samples collected in 4 mL EDTA vacutainers from 1997 to 2012. DNA was extracted using the Qiagen® FlexiGene® DNA kit. The average storage duration at -30°C was 12 years. The quality and quantity of the isolated DNA were assessed using spectrophotometry (NanoDrop™), a fluorometric assay for double-stranded DNA (Qubit™), and agarose gel electrophoresis. The mean DNA yield per sample was found to be 114 µg from whole blood volumes that ranged from 0.5 to 4 mL. The mean A260/280 ratio and median A260/280 ratios were both 1.8. No correlation was found between the duration of storage and the total yield or the quality of DNA extracted. These data suggest that high-quality DNA can be extracted from whole blood samples that are stored at -30°C for up to 19 years.