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  Table of Contents  
Year : 2016  |  Volume : 53  |  Issue : 2  |  Page : 304-308

Place of birth and risk of gallbladder cancer in India

1 Centre for Cancer Epidemiology, Tata Memorial Centre, Mumbai, Maharashtra, India
2 Chiplunkar Lab, Advanced Center for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India
3 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Mumbai, Maharashtra, India
5 Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France
6 Centre for Global Health, National Cancer Institute, NIH, DHSS, Bethesda, USA

Date of Web Publication6-Jan-2017

Correspondence Address:
R Dikshit
Centre for Cancer Epidemiology, Tata Memorial Centre, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.197723

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 » Abstract 

Context: Within India, the incidence of gallbladder cancer (GBC) is characterized by marked geographical variation; however, the reasons for these differences are unclear. AIMS: To evaluate the role of place of birth, length of residence, and effect of migration from high- to low-risk region on GBC development. Settings and Design: Population-based cancer registries (PBCRs); case–control study. Subjects and Methods: 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. Statistical Analysis: 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. Results: 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). Conclusions: 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.

Keywords: Birth region, gallbladder cancer, population-based cancer registries

How to cite this article:
Mhatre S S, Nagrani R T, Budukh A, Chiplunkar S, Badwe R, Patil P, Laversanne M, Rajaraman P, Bray F, Dikshit R. Place of birth and risk of gallbladder cancer in India. Indian J Cancer 2016;53:304-8

How to cite this URL:
Mhatre S S, Nagrani R T, Budukh A, Chiplunkar S, Badwe R, Patil P, Laversanne M, Rajaraman P, Bray F, Dikshit R. Place of birth and risk of gallbladder cancer in India. Indian J Cancer [serial online] 2016 [cited 2021 Dec 6];53:304-8. Available from: https://www.indianjcancer.com/text.asp?2016/53/2/304/197723

 » Introduction Top

Gallbladder cancer (GBC), although generally a rare malignancy, has marked geographical variation both globally and within the Indian subcontinent.[1],[2] The current study was planned to assess the risk of GBC across different regions of India and to evaluate the role of birthplace, length of residence in high-risk region, and effect of migration from high to low-risk region in the development of GBC.

 » Subjects and Methods Top

Data extraction from population-based cancer registries

We used data from 23 population-based cancer registries (PBCRs)[2] to quantify geographical variation in GBC incidence within India. PBCRs were assigned to one of the five different geographical zones based on their location in India, i.e. North, Northeast, Central, West, and South.

Case–control study

We conducted a hospital-based case–control study of GBC at Tata Memorial Hospital (TMH), Mumbai, from September 2010 to June 2015. The study was approved by the TMH Institutional Review Board. We enrolled 1170 GBC cases and 2525 controls during this period. Cases were histopathologically/cytologically confirmed men or women with primary GBC (International Classification of Diseases for Oncology Version 3 site code C24) visiting TMH for diagnosis and/or treatment. Controls enrolled in the study were visitors to patients in TMH with cancers other than biliary tract cancer. The proportion of controls from visitors for any individual cancer site was not more than 20%, with the majority of controls being friends, neighbors, colleagues, in-laws, and spouses. Controls were frequency matched to cases on age (±10 years), gender, and region of residence at the time of enrolment. For regional matching, India was divided into five regions which are as follows: North (Uttar Pradesh, Bihar, Delhi, Haryana, Himachal Pradesh, Jammu and Kashmir, Punjab, Rajasthan, Chandigarh, and Uttarakhand), Northeast (Arunachal Pradesh, Assam, Meghalaya, Nagaland, Manipur, Tripura, West Bengal, Jharkhand, and Orissa), West (Goa, Gujarat, Daman and Diu, Dadra and Nagar Haveli, Maharashtra), South (Andhra Pradesh, Karnataka, Kerala, Lakshadweep, Andaman and Nicobar, Tamil Nadu, Telangana), and Central (Madhya Pradesh and Chhattisgarh).

Exposure assessment

Definition of high- and low-risk regions

To quantify the geographical variation in GBC incidence, we divided Indian states and territories into high- and low-risk regions using incidence rates extracted from PBCRs. States were considered to be in high-risk region if PBCR existing in the state observed average age-adjusted rates of >5.0 per 100,000 persons.[2] All other PBCR states were considered as low-risk regions. In states with no cancer registry, we used the microscopic age-adjusted incident rate provided by the  Atlas More Details of cancer in India [3] to classify the states into high- and low-risk regions using the same threshold of incidence rate. Thus, Bihar, Delhi, Himachal Pradesh, Punjab, Chandigarh, Rajasthan, Uttarakhand, Uttar Pradesh, Assam, Tripura, Sikkim, Jharkhand, and West Bengal were categorized into high-risk regions (mainly North Indian states) and the remaining states classified as low-risk regions.

Other exposure variables

We used questionnaire data from the case–control study to adjust for potential confounders. The questionnaire for case–control study included detailed information on lifestyle risk factors such as diet, tobacco and alcohol usage, gallstone history, and reproductive history. In addition, detailed anthropometric measurements were recorded for all study participants. All anthropometric measurements were done twice in succession and averaged for the final value.


Detailed statistical analysis was performed on both cancer registry and case–control data. Analyses were performed using the Statistical Package Stata SE 12 (StataCorp LP, College Station, TX, USA).

Cancer registry data

We extracted gender-specific age-standardized incidence rates per 100,000 person-years for 23 different PBCRs included in the National Cancer Registry Programme. The Chennai Cancer Registry is high quality and of longest duration; registry with one of the lowest rates of GBC was used as reference category to estimate rate ratios (RRs) for each registry.[2] RRs for each registry were estimated.[4]

Case–control study data

Odds ratios (ORs) and their associated 95% confidence intervals (CIs) for developing GBC in high-risk region compared to low-risk region were estimated through unconditional logistic regression models using hospital-based case–control study. To estimate the effect of length of residence in a high-risk region, we stratified study participants from the hospital-based case–control study into the following mutually exclusive categories:

  • Never lived in a GBC high-risk region (reference)
  • Lived for a minimum of 1 year but <20 years in a GBC high-risk region
  • Lived for 20 and more than 20 years but less than a lifetime in a GBC high-risk region
  • Lifetime: If study participant has lived the entire course of his/her life in a GBC high-risk region.

Effect of migration on GBC risk was estimated by comparing the study participants born in high-risk region and then migrated to low-risk region at any point in their life course to those are not migrated in their entire life course.

Models were adjusted for potential confounders; age (continuous), education (<5 years of schooling, ≥5 years of education), current residential region (North, Northeast, Central, West, and South), gender, gallstone history (present/not present), waist to hip ratio (continuous), smoking and smokeless tobacco usage (yes/no), and number of full-term pregnancies as continuous (women).

 » Results Top

GBC incidence showed geographical variation in India [Graph 1] and [Graph 2]. Kamrup Registry in the Northeast zone of India showed the highest RR (men: 3.61 and women: 7.18) compared to the the Chennai Cancer Registry in Southern India. The RR for registries in North and Northeast varied from 0.38–3.61 for men to 1.26–7.18 from women while registries from South showed lowest risk [Graph 1] and [Graph 2].

The results of case–control study showed risk in both high- and low-risk regions [Table 1] and [Table 2]. [Table 1] shows demographic information for participants enrolled in the hospital-based case–control study. The mean age for cases and controls was observed to be 49.85 and 46.03 years, respectively. Cases more often reported current residence in the North and Northeast region, with the smallest proportion of cases residing in South India.
Table 1: Selected characteristics of study participants by case–control status

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Table 2: Length of residence in high risk region and risk of developing GBC: Estimates from case-control study in Mumbai (2010-2015)

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The OR of developing GBC for those reporting birth in a high-risk region was observed to be 4.82 (95% CI: 3.87–5.99) compared to those born in low-risk region, after adjusting for potential confounders. The observed risk was much stronger in women (OR = 6.04; 95% CI: 4.52–8.07) compared to men (OR = 3.17; 95% CI: 2.23–4.50). Risk increased with increasing duration of residence in a high-risk region. The risk was maximum for those who always/lifetime lived in a high-risk region compared to those who never lived in high-risk region (OR = 5.58; 95% CI: 4.42–7.05). Study participants born in high-risk region reported high susceptibility of GBC even after migration from high- to low-risk region (OR = 1.36; 95% CI: 1.02–1.82) [Table 2].

 » Discussions Top

The current study using data from cancer registries demonstrates marked geographical variation in GBC risk, with the highest risks observed in registries from North and Northeast regions compared to the registries in South India. These results are based on 23 well functional PBCRs data. Some of these registries have also met the criteria for inclusion in a recent volume of cancer incidence in five continents. To evaluate further whether the higher risk in particular region is because of genetic or environmental factors, we analyzed data from the ongoing case–control study at TMH using information on birthplace and residential histories obtained by personal interviews by trained staff. We observed higher risk of developing GBC if birthplace was in high-risk region compared to that in low-risk region and the risk increased with increase in duration of residence in high-risk region. The increased risk persisted but reduced if individuals migrate from high- to low-risk region indicating either continuing behavioral differences in these individuals or the role of hereditary factors in development of GBC. A large proportion of GBC cases currently residing in low-risk regions were born in a high-risk region (44.81%), suggesting that moderately higher rates in some of low-risk regions (such as Mumbai) might partially be due to migration of population from high-risk regions. The prevalence of possible risk factors [5] such as gallstones,[6] Salmonella More Details typhi,[7] obesity,[8] and heavy metals [9] was observed to be high in high-risk region of GBC (particularly, in North and Northeast regions). It can be thus speculated that differences in the risk of GBC are partly explained by differences in these potential risk factors.

Our study is the first to demonstrate the role of birth place and effect of migration in development of GBC. These findings are based on well-conducted case–control study with stringent quality control measures and after carefully adjusting for potential confounders.

The findings of current study demonstrate need for careful evaluation of possible environmental and genetic factors to estimate the risk attributable to environmental and genetic factors in the development of GBC.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://www.globocan.iarc.fr. [Last cited on 2016 Feb 22].  Back to cited text no. 1
National Cancer Registry Programme. Three Years Report of Population Based Cancer Registries; 2009-2011. New Delhi: Indian Council of Medical Research; 2013.  Back to cited text no. 2
Nandakumar A, Gupta PC, Gangadharan P, Visweswara RN, Parkin DM. Geographic pathology revisited: Development of an atlas of cancer in India. Int J Cancer 2005;116:740-54.  Back to cited text no. 3
Boyle P, Parkin DM. Statistical method of registries. In: Jensen OM, Parkin DM, MacLennan R, Muir CS, Skeet RG, editors. Cancer Registration: Principles and Methods. 95th ed. Lyon: International Agency for Research on Cancer; 1991. p. 126-58.  Back to cited text no. 4
Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: Geographical distribution and risk factors. Int J Cancer 2006;118:1591-602.  Back to cited text no. 5
Malhotra SL. Epidemiological study of cholelithiasis among railroad workers in India with special reference to causation. Gut 1968;9:290-5.  Back to cited text no. 6
Kothari A, Pruthi A, Chugh TD. The burden of enteric fever. J Infect Dev Ctries 2008;2:253-9.  Back to cited text no. 7
International Institute of Population Sciences. State Fact Sheets of NHFS-3. IIPs and Macro ORC; 2006. Available from: http://www.iipsindia.org/factsheets.html. [Last accessed on 2016 Feb 22].  Back to cited text no. 8
Unisa S, Jagannath P, Dhir V, Khandelwal C, Sarangi L, Roy TK. Population-based study to estimate prevalence and determine risk factors of gallbladder diseases in the rural Gangetic basin of North India. HPB (Oxford) 2011;13:117-25.  Back to cited text no. 9


  [Table 1], [Table 2]

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