- Email: [email protected]
Genetics of gallbladder cancer
Correspondence
Genetics of gallbladder cancer Sharayu Mhatre and colleagues1 published the first genomewide association study (GWAS) on gall bladder cancer and found a strong, replicated association at chromosome 7q21.12, which harbours ATP binding cassette sub family B genes ABCB1 and ABCB4. The authors additionally estimated the combined heritability of the GWAS data using the Genome-Wide Complex Trait Analysis tool, and reported that their data explain 23% of gallbladder cancer risk variation, corresponding to a familial relative risk (FRR) of 3·15. Such estimates have been reported for several cancers, but these have additionally reported the empirical FRRs from family studies and have provided an estimation on the proportions of FRRs explained by the GWAS data.2,3 The estimates generated for 14 different cancers showed a range from 5% to 60% of the empirical FRRs explained by the published GWAS data.2,3 The paper by Mhatre and colleagues did not provide data for empirical FRRs, obviously because no FRR estimates on gallbladder cancer were available for the Indian population, which is known to have a high incidence of this cancer, also found in Indian immigrants to Sweden.1,4 The comparison to empirical FRR would have been particularly relevant because the GWAS-derived estimate for FRR of 3·15 is the highest so far Observed number
SIR (95% CI)
Parents
25
2·47 (1·59–3·65)*
Father
3
1·22 (0·23–3·61)
Mother
22
2·83 (1·77–4·29)*
Observed number is number of offspring with familial gallbladder cancer. *95% CI does not include 1·00.
Table: Standardised incidence ratios (SIRs) for gallbladder cancer in offspring of parents diagnosed with gallbladder cancer (follow-up, 1961–2012)
www.thelancet.com/oncology Vol 18 June 2017
reported for any cancer; for most cancers, the GWAS derived estimates were around 1·50, with exception of testicular cancer (3·09) and osteosarcoma (2·90).3 FRRs for gallbladder cancer are available from our study based on the Swedish Family-Cancer Database.5 This database covered 10·2 million individuals who were followed up between 1961 and 1998. More than 7000 gallbladder cancers were diagnosed and FRRs were estimated by the standardised incidence ratios (SIR~ FRR). Gallbladder cancer showed a high familial risk of 5·05 for the 10 offspring (maximal age 66 years) of affected parents.5 We updated here the results by extending the followup to the end of year 2012 covering more than 11 000 gallbladder cancers. 25 offspring (maximal age 80 years) were diagnosed with familial gallbladder cancer (table). The overall SIR remained significant, but it was decreased to 2·47. A significant association was noted only for offspring whose mothers were diagnosed with gallbladder cancer (2·83), suggesting preferential maternal transmission of the disease risk. The decrease in SIR between the two analyses was most likely due to the relatively young age of offspring (thus high FRR) in the first analysis and low number of cases (wide confidence intervals). Although the Swedish SIRs for gallbladder cancer might not be valid for the Indian population, they do show that gallbladder cancer might be familial. A surprising finding, however, is that our empirical familial risk of 2·47 was lower than the high GWAS predicted FRR of 3·15, generated by Mhatre and colleagues.1 The Swedish data raise a question about sexspecific GWAS results because in India as well as elsewhere the female incidence of gallbladder cancer far exceeds the male incidence. It would have been of interest to see sexspecific GWAS results rather than sexadjusted results.
AH is a shareholder in Targovax ASA and an employee and shareholder in TILT Biotherapeutics Ltd. AH is Jane and Aatos Erkko Professor of Oncology at the University of Helsinki. This work was funded by the German Cancer Aid, the EU Transcan funding by the German Federal Ministry of Education and Research, Jane and Aatos Erkko Foundation, University of Helsinki and Helsinki University Central Hospital, and the Swedish Research Council for Health, Working Life and Welfare (in Swedish: FORTE; Reg. no. 2013-1836), and FORTE (Reg. no. 2014-0804) and the Swedish Research Council (2012-2378 and 2014-10134) as well as ALF funding from Region Skåne. Other authors declare no competing interests.
*Kari Hemminki, Akseli Hemminki, Asta Försti, Kristina Sundquist, Xinjun Li [email protected] Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany (KH, AF); Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Finland (AH); Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland (AH); and Center for Primary Health Care Research, Lund University, Malmö, Sweden (KH, AF, KS, XL) 1
2
3
4
5
Mhatre S, Wang Z, Nagrani R, et al. Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study. Lancet Oncol 2017; 18: 535–44. Mitchell JS, Johnson DC, Litchfield K, et al. Implementation of genome-wide complex trait analysis to quantify the heritability in multiple myeloma. Sci Rep 2015; 5: 12473. Sampson JN, Wheeler WA, Yeager M, et al. Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types. J Natl Cancer Inst 2015; 107: djv279. Hemminki K, Mousavi SM, Brandt A, Ji J, Sundquist J. Liver and gallbladder cancer in immigrants to Sweden. Eur J Cancer 2010; 46: 926–31. Hemminki K, Li X. Familial liver and gall bladder cancer: a nationwide epidemiological study from Sweden. Gut 2003; 52: 592–96.
e296
Genetics of gallbladder cancer Sharayu Mhatre and colleagues1 published the first genomewide association study (GWAS) on gall bladder cancer and found a strong, replicated association at chromosome 7q21.12, which harbours ATP binding cassette sub family B genes ABCB1 and ABCB4. The authors additionally estimated the combined heritability of the GWAS data using the Genome-Wide Complex Trait Analysis tool, and reported that their data explain 23% of gallbladder cancer risk variation, corresponding to a familial relative risk (FRR) of 3·15. Such estimates have been reported for several cancers, but these have additionally reported the empirical FRRs from family studies and have provided an estimation on the proportions of FRRs explained by the GWAS data.2,3 The estimates generated for 14 different cancers showed a range from 5% to 60% of the empirical FRRs explained by the published GWAS data.2,3 The paper by Mhatre and colleagues did not provide data for empirical FRRs, obviously because no FRR estimates on gallbladder cancer were available for the Indian population, which is known to have a high incidence of this cancer, also found in Indian immigrants to Sweden.1,4 The comparison to empirical FRR would have been particularly relevant because the GWAS-derived estimate for FRR of 3·15 is the highest so far Observed number
SIR (95% CI)
Parents
25
2·47 (1·59–3·65)*
Father
3
1·22 (0·23–3·61)
Mother
22
2·83 (1·77–4·29)*
Observed number is number of offspring with familial gallbladder cancer. *95% CI does not include 1·00.
Table: Standardised incidence ratios (SIRs) for gallbladder cancer in offspring of parents diagnosed with gallbladder cancer (follow-up, 1961–2012)
www.thelancet.com/oncology Vol 18 June 2017
reported for any cancer; for most cancers, the GWAS derived estimates were around 1·50, with exception of testicular cancer (3·09) and osteosarcoma (2·90).3 FRRs for gallbladder cancer are available from our study based on the Swedish Family-Cancer Database.5 This database covered 10·2 million individuals who were followed up between 1961 and 1998. More than 7000 gallbladder cancers were diagnosed and FRRs were estimated by the standardised incidence ratios (SIR~ FRR). Gallbladder cancer showed a high familial risk of 5·05 for the 10 offspring (maximal age 66 years) of affected parents.5 We updated here the results by extending the followup to the end of year 2012 covering more than 11 000 gallbladder cancers. 25 offspring (maximal age 80 years) were diagnosed with familial gallbladder cancer (table). The overall SIR remained significant, but it was decreased to 2·47. A significant association was noted only for offspring whose mothers were diagnosed with gallbladder cancer (2·83), suggesting preferential maternal transmission of the disease risk. The decrease in SIR between the two analyses was most likely due to the relatively young age of offspring (thus high FRR) in the first analysis and low number of cases (wide confidence intervals). Although the Swedish SIRs for gallbladder cancer might not be valid for the Indian population, they do show that gallbladder cancer might be familial. A surprising finding, however, is that our empirical familial risk of 2·47 was lower than the high GWAS predicted FRR of 3·15, generated by Mhatre and colleagues.1 The Swedish data raise a question about sexspecific GWAS results because in India as well as elsewhere the female incidence of gallbladder cancer far exceeds the male incidence. It would have been of interest to see sexspecific GWAS results rather than sexadjusted results.
AH is a shareholder in Targovax ASA and an employee and shareholder in TILT Biotherapeutics Ltd. AH is Jane and Aatos Erkko Professor of Oncology at the University of Helsinki. This work was funded by the German Cancer Aid, the EU Transcan funding by the German Federal Ministry of Education and Research, Jane and Aatos Erkko Foundation, University of Helsinki and Helsinki University Central Hospital, and the Swedish Research Council for Health, Working Life and Welfare (in Swedish: FORTE; Reg. no. 2013-1836), and FORTE (Reg. no. 2014-0804) and the Swedish Research Council (2012-2378 and 2014-10134) as well as ALF funding from Region Skåne. Other authors declare no competing interests.
*Kari Hemminki, Akseli Hemminki, Asta Försti, Kristina Sundquist, Xinjun Li [email protected] Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany (KH, AF); Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Finland (AH); Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland (AH); and Center for Primary Health Care Research, Lund University, Malmö, Sweden (KH, AF, KS, XL) 1
2
3
4
5
Mhatre S, Wang Z, Nagrani R, et al. Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study. Lancet Oncol 2017; 18: 535–44. Mitchell JS, Johnson DC, Litchfield K, et al. Implementation of genome-wide complex trait analysis to quantify the heritability in multiple myeloma. Sci Rep 2015; 5: 12473. Sampson JN, Wheeler WA, Yeager M, et al. Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types. J Natl Cancer Inst 2015; 107: djv279. Hemminki K, Mousavi SM, Brandt A, Ji J, Sundquist J. Liver and gallbladder cancer in immigrants to Sweden. Eur J Cancer 2010; 46: 926–31. Hemminki K, Li X. Familial liver and gall bladder cancer: a nationwide epidemiological study from Sweden. Gut 2003; 52: 592–96.
e296