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).
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.
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).
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.
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.
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.
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.
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.
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.
South Africa's HIV epidemic has evolved over time in terms of numbers of people living with HIV, access to antiretroviral treatment (ART) and age. These changes have profoundly influenced local ...cancer patterns. The Johannesburg Cancer Study has, over a period of 22 years (1995‐2016), recruited over 20 000 incident black cancer patients who consented to provide answers to a questionnaire and blood samples (serum, DNA). This has presented a unique opportunity to examine the evolving association of HIV with cancer in Africa. We used logistic regression models to explore case‐control associations between specific cancers and HIV, using participants with non‐infection related cancers as controls. Using data of 20 835 cancer patients with confirmed HIV status, we found the following cancers to be associated with HIV: Kaposi's sarcoma (ORadj; 95%CI): (99.1;72.6‐135.1), non‐Hodgkin lymphoma (11.3;9.3‐13.6), cervical cancer (2.7;2.4‐3.0), Hodgkin lymphoma (3.1;2.4‐4.2), cancer of the eye/conjunctiva (18.7;10.1‐34.7), anogenital cancers (anus 2.1;1.4‐3.2, penis 5.4;2.7‐10.5, vulva 4.8;3.5‐6.4, vagina 5.5;3.0‐10.2), oropharyngeal cancer (1.6;1.3‐1.9), squamous cell carcinoma of the skin (3.5;2.4‐4.9), melanoma (2.0;1.2‐3.5) and cancer of the larynx (1.7;1.3‐2.4). Kaposi's sarcoma odds ratios increased from the pre‐ART (1995‐2004) to the early ART (2005‐2009) period but declined in the late ART (2010‐2016) period. Odds ratios for cancers of the eye/conjunctiva, cervix, penis and vulva continued to increase in recent ART periods. Our study confirms the spectrum of HIV‐associated cancers found in other African settings. The odds ratios of conjunctival and HPV‐related cancers continue to rise in the ART era as the HIV positive population ages.
What's new?
In South Africa, the changing shape of the HIV epidemic has also shifted patterns of cancer. Here, the authors studied the association between HIV infection and cancer incidence over a 22‐year period. More than 20,000 black cancer patients participated, contributing information about HIV infection status, lifestyle and behavior, and other risk factors. The researchers found that 13 cancers were associated with HIV infection. As antiretroviral treatments become more available and the population living with HIV ages, odds ratios of HPV‐related cancers and conjunctival cancer have risen, suggesting a need for education and surveillance among people living with HIV.
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.
...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.
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.
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.
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.
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.
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.
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.
Kaposi sarcoma‐associated herpesvirus (KSHV) causes Kaposi sarcoma (KS). The risk of KS is amplified in HIV‐immunosuppressed individuals and antiretroviral therapy (ART) reduces KS incidence. ...Reliable data on the relationship between these factors are lacking in Africa. We used questionnaires and serum from 7886 black South Africans (18‐74 years) with incident cancer, recruited between 1995 and 2016. ART rollout started in 2004. We measured associations between KS, HIV‐1 and KSHV before and after ART rollout. We measured seropositivity to HIV‐1, KSHV latency‐associated nuclear antigen (LANA) and glycoprotein (K8.1) and calculated case‐control‐adjusted odds ratios (ORadj) and 95% confidence intervals (CI) in relation to KS and KSHV infection, before (1995‐2004), early (2005‐2009) and late (2010‐2016) ART rollout periods. KSHV seropositivity among 1237 KS cases was 98%. Among 6649 controls, KSHV seropositivity was higher in males (ORadj = 1.4 95%CI 1.23‐1.52), in persons with HIV, (ORadj = 4.2 95%CI 3.74‐4.73) and lower in high school leavers (ORadj = 0.7 95%CI 0.59‐0.83). KSHV seropositivity declined over the three ART rollout periods (37%, 28% and 28%, Ptrend < .001) coinciding with increases in high school leavers over the same periods (46%, 58% and 67%, Ptrend < .001). HIV‐1 seroprevalence increased from 10% in the pre‐ART period to 22% in the late ART period (Ptrend < .001). Compared to HIV‐1 and KSHV seronegatives, KSHV seropositives yielded an OR for KS of 26 (95%CI 11‐62) in HIV‐1 seronegative participants and an OR of 2501 (95%CI 1083‐5776) in HIV‐1 seropositive participants. HIV‐1 increases the risk of KS in those infected with KSHV by 100‐fold. Declines in KSHV seroprevalence coincide with ART rollout and with improvements in educational standards and general hygiene.
What's new?
The risk of Kaposi sarcoma, which is caused by Kaposi sarcoma‐associated herpesvirus (KSHV), is amplified in HIV‐immunosuppressed individuals, and antiretroviral therapy (ART) reduces KS incidence. However, reliable data are lacking in Africa. Here, the authors found KS odds ratios for both HIV and KSHV‐seropositive individuals ranging from 2000‐fold in males to 5000‐fold in females compared to seronegative participants. A decline was observed in KSHV antibody positivity levels over the ART period, but not in HIV prevalence. The clinical utility of a serological assay in high‐risk KSHV regions is of limited value unless the specificity of the KSHV assay improves.
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.
In South Africa (SA), liver cancer (LC) is a public health problem and information is limited.
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.
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.
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.
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.
•Cancer cohort recruitment methodology for low resource environment.•20 years of data to identify risk factors for cancer development in black patients.•24 971 black patients with histologically ...proven cancer of any type were enrolled.•Serum and DNA samples are available for serological and genomic analysis.•Viral infections & leading lifestyle risk factors are key in cancer aetiology in SA.
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.
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.
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