Reviewer's report 
 Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional Title: 
study. 
 1  14 March 2005 Version: Date: 
 Arne Åsberg Reviewer: 
Reviewer's report: 
General 
The authors have analysed tissue biopsies from hepatocellular carcinoma patients for HFE mutations. Using the numbers of HFE C282Y homozygotes in this population and in control populations from other studies they have estimated the relative risk of hepatocellular carcinoma in 
HFE C282Y homozygotes. Furthermore, the authors have estimated the lifetime risk for 
hepatocellular carcinoma in HFE C282Y homozygotes. Their population of cases is relatively large, and their reasoning is basically sound. 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
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Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author can be trusted to correct) The proportion of HFE C282Y homozygotes diagnosed with hepatocellular carcinoma depends 
heavily on care of these individuals, i.e. whether they are diagnosed with hemochromatosis in the 
precirrhotic stage and properly followed up. The authors do mention that the population is "well-defined" and that "only a small proportion of HFE C282Y homozygotes have been diagnosed and treated for haemochromatosis". Still, they "found little evidence of undiagnosed 
haemochromatosis-related HCC". As this is a crucial point in generalizing their findings to other 
populations, the authors should more explicitly discuss their findings of penetrance in relation to the area?s health care for hemochromatosis patients in general, and whether the 6 cases with known hemochromatosis were properly treated in the time period before they were diagnosed with 
hepatocellular carcinoma. 
As a measure of relative risk the authors have used the proportion of HFE C282Y homozygotes in 
the population of hepatocellular carcinoma men (8/102) divided by the proportion of HFE C282Y 
homozygotes (men and women) in the control population (9/1508). This is not an ordinary measure 
of relative risk. In this respect, the study is a case-control study, so the proper measure of relative 
risk is the odds ratio. The authors state "Our results show that the frequency of HFE C282Y homozygosity in the male HCC cohort was 13 times higher than that in the control cohort the HFE C282Y homozygous 
genotype is therefore a significant cause of liver cancer." Association is not a proof of causality, so 
this sentence is better changed. The first sentence in "Histology" in "Results" should refer to Table 3 instead of Table 2. The term "HCC" is explained in Table 3 but not in Table 2, and the terms "Stage" and "Grade" are 
not explained in Table 3. 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
Some repetitions of results appear in "Discussion". 
The last sentence in "Histology" in "Results" could be moved to "Methods". 
 Accept after minor essential revisions What next?: 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare that I have no competing interests 
Reviewer's report 
 Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional Title: 
study. 
 1  14 March 2005 Version: Date: 
 Arne Åsberg Reviewer: 
Reviewer's report: 
General 
The authors have analysed tissue biopsies from hepatocellular carcinoma patients for HFE mutations. Using the numbers of HFE C282Y homozygotes in this population and in control populations from other studies they have estimated the relative risk of hepatocellular carcinoma in 
HFE C282Y homozygotes. Furthermore, the authors have estimated the lifetime risk for 
hepatocellular carcinoma in HFE C282Y homozygotes. Their population of cases is relatively large, and their reasoning is basically sound. 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author can be trusted to correct) The proportion of HFE C282Y homozygotes diagnosed with hepatocellular carcinoma depends 
heavily on care of these individuals, i.e. whether they are diagnosed with hemochromatosis in the 
precirrhotic stage and properly followed up. The authors do mention that the population is "well-defined" and that "only a small proportion of HFE C282Y homozygotes have been diagnosed and treated for haemochromatosis". Still, they "found little evidence of undiagnosed 
haemochromatosis-related HCC". As this is a crucial point in generalizing their findings to other 
populations, the authors should more explicitly discuss their findings of penetrance in relation to the area?s health care for hemochromatosis patients in general, and whether the 6 cases with known hemochromatosis were properly treated in the time period before they were diagnosed with 
hepatocellular carcinoma. 
As a measure of relative risk the authors have used the proportion of HFE C282Y homozygotes in 
the population of hepatocellular carcinoma men (8/102) divided by the proportion of HFE C282Y 
homozygotes (men and women) in the control population (9/1508). This is not an ordinary measure 
of relative risk. In this respect, the study is a case-control study, so the proper measure of relative 
risk is the odds ratio. The authors state "Our results show that the frequency of HFE C282Y homozygosity in the male HCC cohort was 13 times higher than that in the control cohort the HFE C282Y homozygous 
genotype is therefore a significant cause of liver cancer." Association is not a proof of causality, so 
this sentence is better changed. The first sentence in "Histology" in "Results" should refer to Table 3 instead of Table 2. The term "HCC" is explained in Table 3 but not in Table 2, and the terms "Stage" and "Grade" are 
not explained in Table 3. 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
Some repetitions of results appear in "Discussion". 
The last sentence in "Histology" in "Results" could be moved to "Methods". 
 Accept after minor essential revisions What next?: 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare that I have no competing interests 
Please review this paper.
user
Reviewer's report 
 Hepatocellular carcinoma and the penetrance of HFE C282Y mutations: a cross sectional Title: 
study. 
 1  14 March 2005 Version: Date: 
 Arne Åsberg Reviewer: 
Reviewer's report: 
General 
The authors have analysed tissue biopsies from hepatocellular carcinoma patients for HFE mutations. Using the numbers of HFE C282Y homozygotes in this population and in control populations from other studies they have estimated the relative risk of hepatocellular carcinoma in 
HFE C282Y homozygotes. Furthermore, the authors have estimated the lifetime risk for 
hepatocellular carcinoma in HFE C282Y homozygotes. Their population of cases is relatively large, and their reasoning is basically sound. 
------------------------------------------------------------------------------- 
Major Compulsory Revisions (that the author must respond to before a decision on publication can be reached) 
------------------------------------------------------------------------------- 
Minor Essential Revisions (such as missing labels on figures, or the wrong use of a term, which the author can be trusted to correct) The proportion of HFE C282Y homozygotes diagnosed with hepatocellular carcinoma depends 
heavily on care of these individuals, i.e. whether they are diagnosed with hemochromatosis in the 
precirrhotic stage and properly followed up. The authors do mention that the population is "well-defined" and that "only a small proportion of HFE C282Y homozygotes have been diagnosed and treated for haemochromatosis". Still, they "found little evidence of undiagnosed 
haemochromatosis-related HCC". As this is a crucial point in generalizing their findings to other 
populations, the authors should more explicitly discuss their findings of penetrance in relation to the area?s health care for hemochromatosis patients in general, and whether the 6 cases with known hemochromatosis were properly treated in the time period before they were diagnosed with 
hepatocellular carcinoma. 
As a measure of relative risk the authors have used the proportion of HFE C282Y homozygotes in 
the population of hepatocellular carcinoma men (8/102) divided by the proportion of HFE C282Y 
homozygotes (men and women) in the control population (9/1508). This is not an ordinary measure 
of relative risk. In this respect, the study is a case-control study, so the proper measure of relative 
risk is the odds ratio. The authors state "Our results show that the frequency of HFE C282Y homozygosity in the male HCC cohort was 13 times higher than that in the control cohort the HFE C282Y homozygous 
genotype is therefore a significant cause of liver cancer." Association is not a proof of causality, so 
this sentence is better changed. The first sentence in "Histology" in "Results" should refer to Table 3 instead of Table 2. The term "HCC" is explained in Table 3 but not in Table 2, and the terms "Stage" and "Grade" are 
not explained in Table 3. 
------------------------------------------------------------------------------- 
Discretionary Revisions (which the author can choose to ignore) 
Some repetitions of results appear in "Discussion". 
The last sentence in "Histology" in "Results" could be moved to "Methods". 
 Accept after minor essential revisions What next?: 
 An article whose findings are important to those with closely related research Level of interest: 
interests 
 Acceptable Quality of written English: 
 No Statistical review: 
Declaration of competing interests: 
I declare that I have no competing interests 
assistant