Center for Cancer Epidemiology

Victoria, Australia

Center for Cancer Epidemiology

Victoria, Australia

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Mhatre S.,Center for Cancer Epidemiology | Wang Z.,St Jude Childrens Research Hospital | Nagrani R.,Center for Cancer Epidemiology | Badwe R.,Tata Memorial Hospital | And 11 more authors.
The Lancet Oncology | Year: 2017

Background Gallbladder cancer is highly lethal, with notable differences in incidence by geography and ethnic background. The aim of this study was to identify common genetic susceptibility alleles for gallbladder cancer. Methods In this case-control genome-wide association study (GWAS), we did a genome-wide scan of gallbladder cancer cases and hospital visitor controls, both of Indian descent, followed by imputation across the genome. Cases were patients aged 20–80 years with microscopically confirmed primary gallbladder cancer diagnosed or treated at Tata Memorial Hospital, Mumbai, India, and enrolled in the study between Sept 12, 2010, and June 8, 2015. We only included patients who had been diagnosed less than 1 year before the date of enrolment and excluded patients with any other malignancies. We recruited visitor controls aged 20–80 years with no history of cancer visiting all departments or units of Tata Memorial Hospital during the same time period and frequency matched them to cases on the basis of age, sex, and current region of residence. We estimated association using logistic regression, adjusting for age, sex, and five eigenvectors. We recruited samples for a replication cohort from patients visiting Tata Memorial Hospital between Aug 4, 2015, and May 17, 2016, and patients visiting the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, between July, 2010, and May, 2015. We used the same inclusion and exclusion criteria for the replication set. We examined three of the most significant single-nucleotide polymorphisms (SNPs) in the replication cohort and did a meta-analysis of the GWAS discovery and replication sets to get combined estimates of association. Findings The discovery cohort comprised 1042 gallbladder cancer cases and 1709 controls and the replication cohort contained 428 gallbladder cancer cases and 420 controls. We observed genome-wide significant associations for several markers in the chromosomal region 7q21.12 harbouring both the ABCB1 and ABCB4 genes, with the most notable SNPs after replication and meta-analysis being rs1558375 (GWAS p=3·8 × 10−9; replication p=0·01; combined p=2·3 × 10−10); rs17209837 (GWAS p=2·0 × 10−8; replication p=0·02; combined p=2·3 × 10−9), and rs4148808 (GWAS p=2·4 × 10−8; replication p=0·008; combined p=2·7 × 10−9). Combined estimates of per-allele trend odds ratios were 1·47 (95% CI 1·30–1·66; p=2·31 × 10−10) for rs1558375, 1·61 (1·38–1·89; p=2·26 × 10−9) for rs17209837, and 1·57 (1·35–1·82; p=2·71 × 10−9) for rs4148808. GWAS heritability analysis suggested that common variants are associated with substantial variation in risk of gallbladder cancer (sibling relative risk 3·15 [95% CI 1·80–5·49]). Interpretation To our knowledge, this study is the first report of common genetic variation conferring gallbladder cancer risk at genome-wide significance. This finding, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4, underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer. Funding The Tata Memorial Centre and Department of Biotechnology. © 2017 Elsevier Ltd


PubMed | Dutch Childhood Oncology Group DCOG, Nancy University Hospital Center, National and Kapodistrian University of Athens, University of Turin and 28 more.
Type: | Journal: Frontiers in public health | Year: 2014

The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case-control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10-24years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people.


Royce S.G.,Genetic Epidemiology Laboratory | Alsop K.,Genetic Epidemiology Laboratory | Haydon A.,Monash University | Mead L.,Genetic Epidemiology Laboratory | And 6 more authors.
Colorectal Disease | Year: 2010

Objective: Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied. Method: We analysed 109 tumours from a population-based case-family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early-onset colorectal cancer had been previously screened for germ-line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGFβRII) and somatic k-ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real-time PCR. Results: Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGFβR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade. Conclusion: Loss of SMAD4 expression is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age-groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early-onset colorectal cancer only explain a small proportion of the disease and require further exploration. © 2010 The Authors. Journal Compilation © 2010 The Association of Coloproctology of Great Britain and Ireland.


PubMed | International Agency for Research on Cancer, Advanced Center for Treatment, Tata Memorial Hospital, Mount Sinai Hospital and 2 more.
Type: | Journal: European journal of cancer (Oxford, England : 1990) | Year: 2016

Current evidence suggests that the relationship between obesity and breast cancer (BC) risk may vary between ethnic groups.A total of 1633 BC cases and 1504 controls were enrolled in hospital-based case-control study in Mumbai, India, from 2009 to 2013. Along with detailed questionnaire, we collected anthropometric measurements on all participants. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence interval (CI) for BC risk associated with anthropometry measurements, stratified on tumour subtype and menopausal status.Waist-to-hip ratio (WHR) of 0.95 was strongly associated with risk of BC compared to WHR 0.84 in both premenopausal (OR=4.3; 95% CI: 2.9-6.3) and postmenopausal women (OR=3.4; 95% CI: 2.4-4.8) after adjustment for body mass index (BMI). Premenopausal women with a BMI 30 were at lower risk compared to women with normal BMI (OR=0.5; 95% CI: 0.4-0.8). A similar protective effect was observed in women who were postmenopausal for <10 years (OR=0.6; 95% CI: 0.4-0.9) but not in women who were postmenopausal for 10 years (OR=1.8; 95% CI: 1.1-3.3). Overweight and obese women (BMI: 25-29.9 and30kg/m(2), respectively) were at increased BC risk irrespective of menopausal status if their WHR 0.95. Central obesity (measured in terms of WC and WHR) increased the risk of both premenopausal and postmenopausal BCs irrespective of hormone receptor (HR) status.Central obesity appears to be a key risk factor for BC irrespective of menopausal or HR status in Indian women with no history of hormone replacement therapy.


PubMed | International Agency for Research on Cancer, U.S. National Cancer Institute, Center for Cancer Epidemiology, Tata Memorial Hospital and Advanced Center for Treatment
Type: Journal Article | Journal: Indian journal of cancer | Year: 2017

Within India, the incidence of gallbladder cancer (GBC) is characterized by marked geographical variation; however, the reasons for these differences are unclear.To evaluate the role of place of birth, length of residence, and effect of migration from high- to low-risk region on GBC development.Population-based cancer registries (PBCRs); case-control study.Data of PBCRs were used to demonstrate geographical variation in GBC incidence rates. A case-control study data examined the role of birth place, residence length, and effect of migration in etiology of GBC.Rate ratios for different PBCRs were estimated using Chennai Cancer Registry as the reference population. Odds ratios (ORs) for developing GBC in a high-risk region compared to a low-risk region and associated 95% confidence interval (CI) were estimated through unconditional logistic regression models using case-control study.GBC shows marked variation in incidence with risk highest in Northeast regions and lowest in South India. OR of 4.82 (95% CI: 3.87-5.99) was observed for developing GBC for individuals born in a high-risk region compared to those born in a low-risk region after adjusting for confounders. A dose-response relationship with increased risk with increased length of residence in a high-risk region was observed (OR lifetime 5.58 [95% CI: 4.42-7.05]; Ptrend 0.001). The risk persisted even if study participant migrated from high- to low-risk region (OR = 1.36; 95% CI: 1.02-1.82).The present study signifies the importance of place of birth, length of stay, and effect of migration from high- to low-risk region in the development of GBC. The data indicate role of environmental and genetic factors in etiology of disease.


PubMed | International Agency for Research on Cancer, Womens College Hospital, Tata Memorial Hospital, Mount Sinai Hospital and 2 more.
Type: | Journal: Scientific reports | Year: 2017

To date, no studies have investigated the association of the GWAS-identified SNPs with BC risk in Indian population. We investigated the association of 30 previously reported and replicated BC susceptibility SNPs in 1,204 cases and 1,212 controls from a hospital based case-control study conducted at the Tata Memorial Hospital, Mumbai. As a measure of total susceptibility burden, the polygenic risk score (PRS) for each individual was defined by the weighted sum of genotypes from 21 independent SNPs with weights derived from previously published estimates of association odds-ratios. Logistic regression models were used to assess risk associated with individual SNPs and overall PRS, and stratified by menopausal and receptor status. A total of 11 SNPs from eight genomic regions (FGFR2, 9q31.2, MAP3K, CCND1, ZM1Z1, RAD51L11, ESR1 and UST) showed statistically significant (p-value0.05) evidence of association, either overall or when stratified by menopausal status or hormone receptor status. BC SNPs previously identified in Caucasian population showed evidence of replication in the Indian population mainly with respect to risk of postmenopausal and hormone receptor positive BC.


PubMed | Mount Sinai School of Medicine, International Agency for Research on Cancer, Center for Cancer Epidemiology, Tata Memorial Hospital and U.S. National Cancer Institute
Type: Journal Article | Journal: Cancer causes & control : CCC | Year: 2016

Although cancer registry data indicate that there are large differences in breast cancer (BC) rates between rural and urban regions of India, the reasons for these differences are not well understood.We conducted a hospital based case-control study (1,637 breast cancer cases; 1,515 visitor controls) in Mumbai, India, during the years 2009-2013. Extensive questionnaire data, anthropometry measurement and blood samples were collected on all participants. Using logistic regression models, we estimated risk based on odds ratio (OR) and 95 % confidence intervals (CI) for various reproductive and anthropometric measures, stratified by rural-urban status depending upon residence in first 20 years of life.Waist-to-hip ratio of 0.95 compared to ratio 0.84 was strongly associated with risk of BC in both rural and urban populations (ORurban = 4.10, 95 % CI 3.03-5.56; ORrural = 3.01, 95 % CI 1.85-4.90). First full-term pregnancy after the age of 25 compared to first full-term pregnancy below 20 years of age was associated with risk of BC in both urban and rural women (ORurban = 1.78, 95 % CI 1.32-2.41; ORrural = 2.24, 95 % CI 1.13-4.43). The prevalence of age at first full-term pregnancy was significantly lower in rural (mean age at first full-term pregnancy = 19.39 years) versus urban women (mean age at first full-term pregnancy = 22.62 years), whereas mean waist circumference was much higher in urban women (82.13 cm) compared to rural women (79.26 cm). We did not observe any association between breast feeding and risk of BC.Differences in the prevalence of central adiposity and age at first full-term pregnancy between rural and urban women from India may explain some differences in breast cancer rates between these two populations.


Park D.J.,University of Melbourne | Lesueur F.,International Agency for Research on Cancer | Nguyen-Dumont T.,University of Melbourne | Pertesi M.,International Agency for Research on Cancer | And 25 more authors.
American Journal of Human Genetics | Year: 2012

An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases. © 2012 The American Society of Human Genetics.


Nagrani R.T.,Center for Cancer Epidemiology | Budukh A.,Center for Cancer Epidemiology | Koyande S.,Mumbai Cancer Registry | Panse N.S.,Nargis Dutt Memorial Cancer Hospital | And 2 more authors.
Indian Journal of Cancer | Year: 2014

Context: Breast cancer incidence rates are high in developed countries and much lower in less developed countries including India. Aims: The aim of the following study is to compare breast cancer incidence rates in rural, urban and metro regions of India and to estimate risk of developing breast cancer associated with residence in a rural area. Settings and Design: Descriptive and analytical study design. Materials and Methods: We extracted age adjusted incidence rate from 26 population-based cancer registries and data from hospital-based case-control study to estimate rate and risk ratio for developing breast cancer in an urban region compared with a rural residence. Statistical Analysis: The rate ratios and 95% confidence interval (CI) for developing breast cancer in the urban and metro region compared with rural registry of Barshi were estimated. The odds ratio (OR) and 95% CI for developing breast cancer in women residing in a rural region was estimated by fitting unconditional logistic regression using hospital-based case-control study data. Average annual percentage change in most recent 15 years (1996-2010) for Barshi (rural), Aurangabad (urban), and Mumbai (metro) cancer registry was obtained by fitting a log-linear model using joint point regression. Results: Living first 20 years of life in a rural area reduces the risk of breast cancer (OR = 0.65, 95% CI: 0.56-0.76). Conclusions: The current study demonstrates that lifestyle operative in a rural area is protective against risk of developing breast cancer.


PubMed | Center for Cancer Epidemiology
Type: Journal Article | Journal: Indian journal of cancer | Year: 2014

Context: Breast cancer incidence rates are high in developed countries and much lower in less developed countries including India. Aims: The aim of the following study is to compare breast cancer incidence rates in rural, urban and metro regions of India and to estimate risk of developing breast cancer associated with residence in a rural area. Settings and Design: Descriptive and analytical study design. Materials and Methods: We extracted age adjusted incidence rate from 26 population-based cancer registries and data from hospital-based case-control study to estimate rate and risk ratio for developing breast cancer in an urban region compared with a rural residence. Statistical Analysis: The rate ratios and 95% confidence interval (CI) for developing breast cancer in the urban and metro region compared with rural registry of Barshi were estimated. The odds ratio (OR) and 95% CI for developing breast cancer in women residing in a rural region was estimated by fitting unconditional logistic regression using hospital-based case-control study data. Average annual percentage change in most recent 15 years (1996-2010) for Barshi (rural), Aurangabad (urban), and Mumbai (metro) cancer registry was obtained by fitting a log-linear model using joint point regression. Results: Living first 20 years of life in a rural area reduces the risk of breast cancer (OR = 0.65, 95% CI: 0.56-0.76). Conclusions: The current study demonstrates that lifestyle operative in a rural area is protective against risk of developing breast cancer.

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