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Keywords:

  • adolescence;
  • obesity;
  • gastroesophageal cancer;
  • socioeconomic status

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

To the authors' knowledge, little work has been done concerning adolescent precursors for gastroesophageal cancer. In the current study, the association of adolescent overweight as well as socioeconomic status (SES) with the incidence of esophageal adenocarcinoma (EAC), gastroesophageal junction adenocarcinoma (GEJAC), and noncardia gastric cancer (NCGC) was evaluated.

METHODS

Body mass index (BMI) was measured in 1 million Israeli adolescent males who underwent a general health examination at a mean age of 17.3 ± 0.5 years from 1967 to 2005. Overweight was defined as a BMI ≥ 85th percentile of the standard US distribution in adolescence. Incident cancer was identified by linkage with the Israeli National Cancer Registry.

RESULTS

A total of 182 incident cancer cases were documented (52 combined EAC and GEJAC cases and 130 NCGC cases). Adolescent overweight at baseline (BMI ≥ 85th percentile) was associated with an increased risk in the combined group of cases of EAC and GEJAC (multivariable hazards ratio [HR], 2.1; 95% confidence interval [95% CI], 1.1-4.3 [P = .032]). Low SES (the lowest category vs the highest) as well as low number of years of education (≤ 9 years) were associated with an increased risk of intestinal-type NCGC (multivariable HR, 2.2; 95% CI, 1.0-4.8 [P = .041] and multivariable HR, 1.9; 95% CI, 1.1-3.19 [P = .020], respectively). The adjusted risk of NCGC was higher in immigrants born in Asian countries and the former Soviet Union.

CONCLUSIONS

Overweight during adolescence was found to be substantially associated with the subsequent development of EAC and GEJAC. In addition, although potential confounding by Helicobacter pylori infection status or lifestyle factors was not fully accounted for in the analyses, lower SES as well as immigration from higher-risk countries are important determinants of NCGC. Cancer 2013;119:4086–4093. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

To the best of our knowledge, little work has been done to examine adolescent precursors or risk factors for gastroesophageal cancer. The US Surveillance, Epidemiology, and End Results data indicate a sharp rise in the incidence of esophageal adenocarcinoma (EAC) as well gastroesophageal junction adenocarcinoma (GEJAC).[1-6] The trend for an increase in EAC, especially among men, also is evident in Europe[6] and Israel.[7] At the same time, the incidence of noncardia gastric cancer (NCGC) demonstrates a continued worldwide trend for decreasing incidence.[1-6]

Adult obesity has been consistently associated with an increased risk of EAC.[8-13] However, to our knowledge studies regarding the impact of obesity at an early age on EAC and GEJAC are scarce and based on distant recall rather than measurement.[14-17] Although an association between low socioeconomic status (SES) and NCGC has been established in both case-control and cohort studies,[18-23] to the best of our knowledge, data regarding the association between SES during adolescence and subsequent risk of cancer also are lacking.

Our group has recently reported on the association between adolescent overweight and colon, pancreatic, uroepithelial, and renal cancer.[24-26] In the current study, we aimed to assess the association between measured body mass index (BMI) in late adolescence as well as SES and ethnic factors and the incidence of EAC, GEJAC, and NCGC in a cohort of over 1 million Jewish Israeli males with 19.9 million person-years of follow-up.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Population

Israeli adolescents are called up to recruitment centers, predominantly at age 17 years, for an obligatory medical board examination to assess their suitability for military service. BMI was not recorded in 3.4% of the examined population and therefore these individuals were excluded. The current study cohort consisted of 1,088,530 Jewish males who were aged 16 years to 19 years at the time of examination between 1967 and 2005 and were born between 1947 and 1978. They were followed for cancer incidence until the end of 2006 by data linkage.

Variable Definitions

Height and weight were measured and recorded during the obligatory medical board examination. Subjects were measured barefoot wearing only a shirt and underwear. The measurements were performed by trained medical personnel using a beam balance and stadiometer. BMI was calculated as weight in kilograms divided by height in meters squared. Excessive body weight among adolescents was defined in relation to the 2000 United States Centers for Disease Control and Prevention (CDC) BMI-for-age growth charts, which are used internationally for reference purposes, as at or above the age and sex-specific 85th percentile of BMI.[27] During adolescence, the threshold of BMI for this definition of overweight is highly dependent on the exact age at the time of examination. At age 16.0 years, the threshold for overweight is 24.2 kg/m2; 8 months later it is 24.8 kg/m2, and at 17.3 years, the threshold is 25.2 kg/m2. Consequently, use of the World Health Organization (WHO) classification of BMI for adults[28] may not be applicable. However, we also undertook a secondary analysis based on the WHO classification.

The SES of the subjects was defined according to their city/town/village of residence at baseline (parental residence). The data that determine the Israeli Central Bureau of Statistics classification of SES on a scale of 1 to 9 include income, dwelling area in meters squared per person, number of siblings, number of cars owned, years of schooling and higher education, and tax payments.[29] We regrouped SES into low (1-3), medium (4-6), and high (6-9) categories. Years of education in late adolescence (≤ 9 years, 10 years, 11 years, and 12 years) served as a personal measure. Other covariate data included height (divided into quintiles), country of birth (grouped as Israel, Asia, North Africa, Europe [including countries of emigration from Europe], and the former Soviet Union), and place of residence (rural or urban). Among the 1,088,530 adolescents included in the current analysis, data were missing in 0.1% for country of birth and years of schooling, in 0.8% for SES, and in 1.3% for place of residence.

Identification of Cancer Cases

We linked the cohort to the Israel National Cancer Registry (INCR) by way of the personal identification number given to all Israeli citizens at the time of birth or immigration. Reporting to the INCR is mandatory since 1982; coverage for solid tumors exceeds 95%.[30, 31] The INCR data include the personal identification number, the date of diagnosis, the site affected, and the International Classification of Diseases code for the tumor and histologic description of the tumor (according to the third edition of the International Classification of Diseases for Oncology). We included only gastroesophageal cancers with a histologic report of adenocarcinoma excluding all other histologic codes. We divided incident cancers into adenocarcinoma occurring in the lower esophagus (EAC; code C15.3), GEJAC (code C16.0), and NCGC (code C16.1-16.9). Because the distinction between GEJAC and EAC tumors is difficult outside the surgical setting, and it is likely that there is extensive misclassification of the sites within cancer registry records,[32, 33] we combined these groups. The analysis of EAC and GEJAC in separate categories is presented in Table 1. The NCGC tumors were further divided into mucinous-type (codes 84813, 84803, and 84903) and intestinal-type.

Table 1. Multivariable Cox Proportional HRs for EAC and GEJAC in 1,088,242 Males
 EAC (N = 28)GEJAC (N = 24)
 No.HRa (95% CI)PNo.HRa (95% CI)P
  1. Abbreviations: 95% CI, 95% confidence interval; BMI, body mass index; CDC, Centers for Disease Control and Prevention; EAC, esophageal adenocarcinoma; GEJAC, gastroesophageal junction adenoma carcinoma; HR, hazards ratio; SES, socioeconomic status; WHO, World Health Organization.

  2. a

    Adjusted.

BMI (CDC)
<85th percentile241 (referent) 161 (referent) 
≥85th percentile41.52 (0.52–4.41).44182.91 (1.15–7.37).024
BMI (WHO)      
<24.9 kg/m2241 (referent) 181 (referent) 
≥25 kg/m241.58 (0.55–4.61).3963.04 (1.20–7.72).019
BMI (WHO)      
<18.5 kg/m221.73 (0.51–5.86).3701.33 (0.30–5.84).69
18.5–24.9 kg/m2221 (referent) 181 (referent) 
25–29.9 kg/m211.43 (0.42–4.78).5721.80 (0.52–6.23).34
≥30 kg/m233.67 (0.49–27.5).20411.9 (3.41–41.70)<.001
  Overall P.50 Overall P.002
SES
High81 (referent) 41 (referent) 
Medium140.58 (0.18–1.85).365151.67 (0.55–5.08).364
Low60.80 (0.33–1.93).62751.06 (0.27–4.07).926
Country of birth
Israel201 (referent) 181 (referent) 
West31.77 (0.51–6.08).36110.64 (0.08–4.87).670
Africa31.32 (0.36–4.73).67031.64 (0.45–5.93).449
Former Soviet Union11.45 (0.19–11.1).71610.99 (0.12–7.68).995
Asia11.06 (0.13–8.20).94911.50 (0.19–11.52).697
No. of y of education
12171 (referent) 151 (referent) 
1120.95 (0.27–3.26).92940.59 (0.13–2.72).506
1020.21 (0.02–1.65).14031.29 (0.45–3.69).627
≤970.78 (0.29–2.09).62920.30 (0.06–1.37).121

Statistical Analysis

The characteristics of the participants are presented as arithmetic means (± the standard deviation) or, in the case of characteristics with skewed distributions, as medians and interquartile ranges. BMI was treated as a dichotomous variable (≥ 85th percentile vs < 85th percentile; ≥ 25 kg/m2 vs < 25 kg/m2) as well as ordinal variable (≥  30 kg/m2, 29.9 kg/m2-25 kg/m2, 24.9 kg/m2-18.5 kg/m2, and < 18.5 kg/m2).Cox proportional hazards models were used to assess associations between the baseline adolescent BMI, as well as height, country of birth, SES, years of education, and urban versus rural place of residence with time to cancer diagnosis. Because the first case of cancer occurred at 2.5 years of follow-up, we used right censoring for this period. Because the year of birth was found to be significantly associated with the incidence of gastroesophageal cancer (EAC and GC: hazards ratio [HR], 1.13 [P = .002] and NCGC: HR, 1.05 [P = .008]), we adjusted for this effect by introducing year of birth into the model in both the univariate and multivariable analyses. Inspection of log minus log plots for each variable verified the assumption of proportionality of the hazards. Analyses were performed using SPSS statistical software (version 19; SPSS Inc, Chicago, Ill).

Ethics

The Israel Defense Forces Medical Corps Institutional Review Board approved the study. After data linkage at the INCR, personal identifiers were permanently deleted from the computer file so that all analyses were undertaken on anonymous records.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Baseline Characteristics

Cohort characteristics at baseline are presented in Table 2. Nearly 82% of all included adolescents were Israeli-born and 8.5% were from the former Soviet Union. The mean age at the time of BMI measurement was 17.3 ± 0.46 years. Excessive body weight at baseline was noted in 12.2% of the adolescents: 9.9% among the first 10 annual examination cohorts and 16.8% in the last 10 cohorts, increasing to 18.3% in the last 3 cohorts. Approximately 25% of the adolescents were classified as being in the low SES category and 11.4 % had the lowest educational level (≤9 years of schooling).

Table 2. Cohort Characteristics at Baseline of 1,088,242 Adolescent Males Examined from 1967 to 2005 and Followed Through 2006
CharacteristicNo. or Mean (SD)
  1. Abbreviations: BMI, body mass index; SD, standard deviation; SES, socioeconomic status; WHO, World Health Organization.

Total cohort1,088,242 (100%)
BMI 
Mean ± SD, kg/m221.5 ± 3.2
BMI by percentile (<85th vs ≥85th) 
No. with <85th percentile955,572 (87.8%)
Mean BMI ± SD, kg/m220.6 ± 2.0
No. with ≥85th percentile132,572 (12.2%)
Mean BMI ± SD, kg/m227.8 ± 2.8
BMI by WHO classification 
<18.5 kg/m271,193 (6.5%)
18.5–24.9 kg/m2870,289 (80.0%)
25–29.9 kg/m284,347 (7.8%)
≥30 kg/m262,413 (5.7%)
SES 
High227,795 (21.1%)
Medium545,413 (50.1%)
Low306,461 (28.4%)
Country of birth 
Israel889,922 (81.8%)
West44,290 (4.1%)
Africa44,828 (4.1%)
Former Soviet Union92,878 (8.5%)
Asia15,550 (1.4%)
No. of y of schooling 
12602,839 (55.5%)
11253,402 (23.3%)
10106,333 (9.80%)
≤9124,424 (11.4%)
Place of residence 
Urban960,030 (89.4%)
Rural113,632 (10.6%)
Age at BMI measurement, y 
Mean ± SD17.3 ± 0.46

Incident Gastroesophageal Cancer

The follow-up ranged from 2.5 years to nearly 40 years, with a mean follow-up of 18.8 ± 10.4 years. During the follow-up period, 182 incident cases were documented: 52 EAC and GEJAC cases and 130 NCGC cases. Of the 130 NCGC cases, 77 (59.2%) were intestinal-type NCGC adenocarcinoma and 53 (40.8%) were of the mucinous type.

BMI at Baseline and Incident Gastroesophageal Cancer

Table 3 presents the Cox proportional hazards analysis for the association between BMI at baseline and the incidence of gastroesophageal cancer according to the US CDC threshold for overweight and obesity (BMI ≥ 85th percentile) as well as according to the WHO classification of overweight and obesity for adults (BMI ≥ 25 kg/m2). Adolescent overweight at baseline, defined as a BMI ≥85th percentile, was found to be significantly associated with an increased risk for the combined EAC and GEJAC group (multivariable HR, 2.1; 95% confidence interval [95% CI], 1.1-4.3 [P = .032]). Similarly, adolescent overweight at baseline, when defined as a BMI ≥ 25 kg/m2, was associated with an increased risk for the combined EAC GEJAC group (multivariable HR, 2.2; 95% CI, 1.1-4.5 [P = .024]). The point estimate of the HR for the combined EAC GEJAC group was further increased when the threshold was raised to a BMI ≥ 30 kg/m2 at baseline (multivariable HR, 7.6; 95% CI, 2.68-21.5 [P < .001]; referent: BMI 18.5 kg/m2-24.9 kg/m2). As stated earlier, we grouped EAC and GEJAC cases together because these cancers are often misclassified[32, 33] and in the current study we could not review the pathology specimens. Analysis of the association between overweight at baseline and EAC and GEJAC separately (Table 1) demonstrated that the risk of cancer was significantly increased for the GEJAC group (BMI ≥ 85th percentile: HR, 2.9; 95%CI, 1.15-7.37 [P = .024]; referent: BMI < 85th percentile), but not for EAC (HR, 1.5; 95% CI, 0.5-4.4 [P = .44]). A BMI ≥ 85th percentile at baseline was not found to be associated with an increased risk of NCGC. Figure 1A shows the cumulative incidence for the combined EAC and GEJAC group and that for NCGC is shown in Figure 1B, according to baseline BMI (>or <85th percentile), adjusted for year of birth, country of birth, SES, and years of education. The mean age at cancer diagnosis did not differ among adolescents with a baseline BMI ≥ 85th percentile compared with adolescents with a BMI <85th percentile for both EAC and GEJAC (median, 51.7 years vs 48.1 years; P = .92) and NCGC (median, 44.0 years vs 45.9 years; P = .62).

image

Figure 1. The cumulative incidence of (A) the combined esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma group and (B) noncardia gastric cancer is shown according to baseline body mass index (BMI) (> 85th percentile or < 85th percentile), adjusted for year of birth, country of birth, socioeconomic status, and years of education.

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Table 3. Multivariable Cox Proportional HRs for Gastroesophageal Cancer in 1,088,242 Males Examined from 1967 to 2005 and Followed Through 2006
 Entire CohortEAC and GEJAC (N = 52)NCGC (N = 130)NCGC Intestinal (N = 77)NCGC Mucinous (N = 53)
 No.No.HRa (95% CI)PNo.HRa (95% CI)PNo.HRa (95% CI)PNo.HRa (95% CI)P
  1. Abbreviations: 95% CI, 95% confidence interval; BMI, body mass index; CDC, Centers for Disease Control and Prevention; EAC, esophageal adenocarcinoma; GEJAC, gastroesophageal junction adenoma carcinoma; HR, hazards ratio; NCGC, noncardia gastric cancer; WHO, World Health Organization.

  2. a

    Adjusted for year of birth, BMI, socioeconomic status, country of birth, and years of education.

  3. b

    BMI categorization performed according to the US CDC percentiles.

  4. c

    BMI categorization performed according to the WHO classification for adults.

BMI (CDCb)             
<85th percentile955,572421 (referent) 1151 (referent) 671 (referent) 481 (referent) 
≥85th percentile132,572102.14 (1.07–4.28).032151.23 (0.72–2.10).46101.40 (0.47- 2.73).3350.99 (0.39–2.34).98
BMI (WHOc)             
<24.9 kg/m2941,482421 (referent) 1121 (referent) 661 (referent) 461 (referent) 
≥25 kg/m2146,760102.23 (1.11–4.47).024181.19 (0.68–2.09).5291.32 (0.65–2.65).4371.03 (0.40–2.60).94
BMI (WHOc)             
<18.5 kg/m271,19321.54 (0.60–3.95).3651.05 (0.56–1.97).8651.14 (0.51–2.51).7400.93 (0.33–2.60).89
18.5–24.9 kg/m2870,289401 (referent) 1071 (referent) 611 (referent) 461 (referent) 
25–29.9 kg/m284,34731.59 (0.66–3.78).29100.98 (0.51–1.89).9761.02 (0.44–2.37).9540.94 (0.33–2.63).91
≥30 kg/m262,41377.60 (2.68–21.5)<.00182.62 (0.96–7.15).0653.41 (1.06–10.95).0331.55 (0.21–11.34).66
   Overall P.002 Overall P.31 Overall P.22 Overall P.97

SES at Baseline and Incident Gastroesophageal Cancer

Table 4 presents the Cox analysis for the association between parental SES at baseline and the incidence of gastroesophageal cancer. Low parental SES at baseline (the lowest category vs the highest) was associated with an increased risk of developing NCGC (univariate HR, 1.95; 95% CI, 1.12-3.40 [P = .01]; and multivariable HR, 1.61; 95% CI, 0.95-2.71 [P = .07]) that was more evident in the intestinal-type tumor (multivariable HR, 2.23; 95% CI, 1.03-4.80 [P = .041]). SES was not found to be associated with the combined EAC and GEJAC group (Fig. 2). Analysis of the association of years of education with the hazards of gastroesophageal cancer revealed that low education (≤ 9 years of schooling) was significantly associated with an increased risk of NCGC (multivariable HR, 1.53; 95% CI, 1.01-2.13 [P = .043]).

image

Figure 2. Hazard ratios (HRs) for the combined esophageal adenocarcinoma (EAC) and gastroesophageal junction adenocarcinoma (GEJAC), noncardia gastric cancer (NCGC), NCGC with intestinal histology, and NCGC with mucinous histology are shown according to baseline socioeconomic status. 95% CI indicates 95% CI.

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Table 4. Multivariable Cox Proportional HRs for Gastroesophageal Cancer in 1,088,242 Males Examined From 1967 to 2005 and Followed Through 2006
 Entire CohortEAC and GEJAC (N = 52)NCGC (N = 130)NCGC Intestinal (N = 77)NCGC Mucinous (N = 53)
 No.No.HRa (95% CI)PNo.HRa (95% CI)PNo.HRa (95% CI)PNo.HRa (95% CI)P
  1. Abbreviations: 95% CI, 95% confidence interval; EAC, esophageal adenocarcinoma; GEJAC, gastroesophageal junction adenoma carcinoma; HR, hazards ratio; NCGC, noncardia gastric cancer; SES, socioeconomic status.

  2. a

    Adjusted for year of birth, BMI, socioeconomic status, country of birth, and years of schooling.

Parental SES
High227,795121 (referent) 181 (referent) 91 (referent) 91 (referent) 
Medium545,413290.75 (0.32–1.77).52691.70 (0.97–2.99).07401.84 (0.89–3.81).09291.17 (0.50–2.76).72
Low306,461101.09 (0.56–2.16).79411.61 (0.95–2.71).07272.23 (1.03–4.80).04141.37 (0.65–2.92).41
   Overall P.59 Overall P.06 Overall P.04 Overall P.64
Country of birth
Israel889,922381.0 (referent) 841.0 (referent) 461.0 (referent) 381.0 (referent) 
West44,29041.23 (0.43–3.49).7071.11 (0.51–2.42).7961.71 (0.72–4.04).2210.36 (0.05–2.66).32
Africa44,82861.47 (0.59–3.63).40171.34 (0.77–2.31).30101.22 (0.60–2.49).5871.48 (0.63–3.47).36
Former Soviet Union92,87821.22 (0.29–5.15).7992.68 (1.33–5.40).00652.79 (1.09–7.14).0342.58 (0.91–7.36).08
Asia15,55021.26 (0.30–5.32).76133.00 (1.64–5.48)<.001103.79 (1.86–7.90)<.00131.78 (0.54–5.92).34
   Overall P.90130Overall P.001 Overall P<.001 Overall P.21
No. of y of education
12602,839321 (referent) 601 (referent) 351 (referent) 251 (referent) 
11253,40270.76 (0.29–2.00).590160.51 (1.01–2.31).12380.48 (0.14–1.57).22380.57 (0.13–1.89).36
10106,33340.68 (0.28–1.65).41091.16 (0.67–1.97).57741.32 (0.67–2.60).42250.98 (0.42–2.28).96
≤9124,42490.54 (0.24–1.22).139451.53 (1.01–2.31).043301.88 (1.10–3.19).020151.12 (0.57–2.20).31
   Overall P.474 Overall P.047 Overall P.025 Overall P.73

Country of Birth and Incident Gastroesophageal Cancer

Table 4 presents the Cox analysis for the association between country of birth and the incidence of gastroesophageal cancer. Place of birth within Asian countries and the former Soviet Union was found to be significantly associated with an increased risk of NCGC (multivariable HR, 3.0; 95% CI, 1.64-5.48 [P < .001] and HR, 2.68; 95% CI, 1.33-5.40 [P = .006], respectively). No association was evident for the combined EAC and GEJAC group.

Height and place of residence (rural vs urban) were not found to be associated with an increased risk of gastroesophageal cancer.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

The main novel observation of the current study is the association between a BMI ≥ 85th percentile during adolescence and future adenocarcinoma of the lower esophagus and gastric cardia. As stated earlier, there is strong evidence to support an association between adult obesity (especially abdominal obesity) and an increased risk of EAC and GEJAC.[8-13, 34, 35] A recently published analysis of pooled data from 12 epidemiological studies demonstrated that BMI was associated with an increased risk of EAC and GEJAC in both men and women and in those with and without symptoms of gastroesophageal reflux disease.[13] However, to the best of our knowledge only 1 prospective study[14] and 3 case-control studies have investigated the effects of BMI at age 20 years on the risk of EAC and GEJAC,[15-17] and these data were obtained by recall. The results of the current study are consistent with these studies.[14-17] A major strength of the current study is the measurement of height and weight at the age of 17 years, thereby minimizing the effects of misreporting BMI, and the near-complete follow-up of all participants through the INCR, thereby minimizing the effects of loss to follow-up. It is interesting to note that the subgroup analysis of the association between overweight at baseline and EAC and GEJAC as separate groups indicated that the risk of cancer was significantly increased only for the GEJAC group. These results should be interpreted with caution because these cancers are prone to misclassification[32, 33] and because of the small number of cases, although the findings are consistent with those of a previous report.[14] Further studies are needed to evaluate whether adolescence obesity is associated more strongly with GEJAC than with EAC. This will be possible with further follow-up of the current study cohort.

The second interesting observation in the current study is the association between low SES in adolescence and the subsequent risk of developing NCGC. The association between low SES and NCGC has been documented in both case-control and cohort studies.[18-23] A strength of the current study is the measurement of SES as both an ecological (data from the Israeli Central Bureau of Statistics) and personal variable (years of education) at a narrow spectrum of age in late adolescence. This association has been attributed to differences in smoking,[36] diet,[37] and Helicobacter pylori infection.[38, 39] SES was reported as one of the most important factors affecting the prevalence of H. pylori infection.[38-40] This phenomenon is of prime importance because infection with H. pylori in known to begin predominantly in childhood and is associated with an increased risk of NCGC.[41-44]

A third finding is that immigration from Asia and the former Soviet Union was strongly associated with an increased risk of intestinal-type NCGC. Immigrants from the former Soviet Union have been reported in previous studies to have an increased risk of gastric cancer.[7, 45, 46] In the current study, immigration occurred up to the age of 19 years and yet the impact on subsequent cancer lasted. One explanation for this observation might relate to differences in H. pylori prevalence.[47-49] A study from Israel reported that the seropositivity was highest among Jewish immigrants from Asia and North Africa and the former Soviet Union (63.2% and 53.8%, respectively); lower among Israeli-born subjects (43.0%); and lowest among subjects originating from North America, Western Europe, and Australia (24.3%).[49] Our report of an increased HR for NCGC among immigrants from countries with the highest levels of H. pylori seroprevalence, Asia and the former Soviet Union (and a Spearman correlation of 0.72 [P = .17] between the HRs for Soviet-born, Asian-born, African-born, European-born, and Israeli-born in the current study and the H. pylori prevalence reported by Muhsen et al[49]), supports the generally accepted hypothesis of the association between H. pylori infection and gastric cancer,[47, 50, 51] and may explain the association noted for country of birth and development of NCGC. Other potential explanations for the disparities according to country of birth could be the role of diet (notably salt intake)[52] and tobacco use,[35, 46, 53] because these factors have been reported to be associated with the development of gastric cancer.[54] One should interpret the results relating to country of birth within the context that immigrants from Asia and the former Soviet Union accounted for a modest number of cases and for only 9.9% of the study sample, although these origins represent > 100,000 subjects.

Potential limitations of the current study include a lack of information about H. pylori status, dietary intake, alcohol consumption, and tobacco use. In the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST) study, the impact of SES on intestinal-type gastric cancer was no longer statistically significant after adjustment for H. pylori seroprevalence.[18] In addition, the negative association between the prevalence of H. pylori infection and the severity of gastrointestinal reflux disease and the incidence of esophageal adenocarcinoma is well documented.[55] Another limitation is the fact that we did not have measurements of abdominal obesity (waist circumference and waist-to-hip ratio) available. This might be important because data have suggested that an increased waist-to-hip ratio is associated with an increased risk of EAC, even among individuals with a normal BMI.[11] In addition, we did not have follow-up measures of BMI: for example, some of the overweight and obese adolescents may have become leaner, although the converse is more likely (ie, some of the adolescents with normal BMI became overweight). This situation is less likely as longitudinal studies consistently report that the likelihood of a persistence of overweight into adulthood is moderate for overweight and obese youth,[56] and people who were not overweight in adolescence may have become so in adulthood. Such misclassification would tend to lead to an underestimation of the associations reported herein. Similarly, it should be noted that SES was measured only once in adolescence and that over the time the SES may change.

In this large cohort, we reported that adolescents with a BMI >  the 85th percentile for their age were at a significantly increased risk of developing EAC and GEJAC. In addition, although confounding by H. pylori infection status or dietary and lifestyle factors may not have been fully accounted for in the analyses, lower SES as well as immigration from higher-risk countries are important determinants of NCGC.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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