Background: Three human polyomaviruses have been classified as probable (Merkel cell polyomavirus) or possible (BK and JC polyomaviruses) carcinogens, but few epidemiologic studies have examined associations between this growing class of viruses and risk of non-Hodgkin lymphoma (NHL).

Methods: Associations between polyomavirus antibodies and NHL incidence were examined using data from the American Cancer Society Cancer Prevention Study-II. This nested case–control study included 279 NHL cases and 557 controls. Prediagnostic antibodies to the major capsid protein of polyomaviruses BKV, JCV, MCV, TSV, WUV, KIV, HPy6, and HPy7 were measured by fluorescent bead-based multiplex serology, and associations with NHL were estimated using conditional logistic regression (NHL overall) and unconditional polytomous logistic regression (NHL subtypes).

Results: Although an inverse trend was suggested for TSV antibody levels and NHL risk, the HRs were not statistically significant. There were no other observed associations between polyomaviruses and NHL risk. For NHL subtypes, TSV antibody level above the median was associated with a lower risk of CLL/SLL; however, this association was based on 19 cases in the high antibody group and may be due to chance.

Conclusions: Our results do not support associations of polyomaviruses BKV, JCV, WUV, KIV, HPyV6, HPyv7, MCV, or TSV with risk of NHL.

Impact: Human polyomavirus antibody levels do not appear to predict a higher NHL risk in immunocompetent individuals. Cancer Epidemiol Biomarkers Prev; 24(2); 477–80. ©2014 AACR.

Polyomaviruses cause common, asymptomatic infections, and antibodies persist throughout life (1). To date, 12 polyomaviruses have been identified, 10 since 2007. A recent International Agency for Research on Cancer panel classified Merkel cell polyomavirus (MCV) as a probable carcinogen and BK and JC polyomaviruses (BKV, JCV) as possible carcinogens (1). In the only three epidemiologic studies (2–4) to examine associations of BKV and JCV antibodies with risk of non-Hodgkin lymphoma (NHL) or NHL subtypes, no associations were found for BKV, but for JCV results were inconsistent. The only study to examine MCV and risk of NHL showed positive associations with some NHL subtypes (4). Because of the limited number of studies to date, we examined associations of plasma antibody levels of JCV, BKV, and MCV—as well as several other polyomaviruses [WU polyomavirus (WUV); KI polyomavirus (KIV); human polyomavirus 6 (HPy6); human polyomavirus 7 (HPy7); Trichodysplasia spinulosa-associated polyomavirus (TSV)]—with risk of NHL in the American Cancer Society (ACS) Cancer Prevention Study-II (CPS-II) Nutrition Cohort, a large prospective study of U.S. men and women.

Participants in this nested case–control study were selected from the subgroup of CPS-II participants who provided a blood sample between 1998 and 2001 (n = 39,371; ref. 5). Lymphomas (n = 279) were reported on biennial questionnaires and verified through medical records (n = 209) or registry linkage (n = 70). NHL subtypes were categorized using INTERLYMPH guidelines (6). For each case, two controls were incidence density matched on sex, race, birth, and blood draw dates (±6 months).

Seroreactivity against BKV, JCV, MCV (isolate 344), TSV, WUV, KIV, HPy6, HPy7 viral capsid protein 1 (VP1) was measured by fluorescent bead-based multiplex serology (1:1000 dilution) at the German Cancer Research Center. In this method, each antigen is carried by a uniquely colored bead. Mixtures of bead sets carrying different antigens are reacted with plasma. A Luminex 100 analyzer quantifies the bead-bound fluorescence-stained human antibodies for each plasma sample and antigen as median fluorescence intensity (MFI; refs. 7, 8). Coefficients of variation for quality control samples were between 1.8% and 5.1%; intraclass correlation coefficients were between 93.6% and 99.7%. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using conditional logistic regression for all NHL, and unconditional polytomous logistic regression (controlling for the matching factors) for the NHL subtypes. Median MFI values for cases and controls were compared using the Wilcoxon rank-sum test. Seropositive MFI values were ≥250. Associations with seropositivity and antibody levels were analyzed for each virus. Cutpoints for the latter analysis were based on quartiles of MFI among seropositive control participants. Cubic splines were used to assess potential nonlinear associations.

The final study population was 836 participants (279 cases, 557 controls), aged 56 to 83 years (median: 70) at blood draw. Median age at NHL diagnosis was 74 years. Controls were slightly more likely than cases to be nonobese (85.3% vs. 83.2%), nonsmokers (49.9% vs. 47.3%), nondrinkers (36.6% vs. 30.8%), and to live in the U.S. Midwest (34.6% vs. 29%), but none of these differences were statistically significant. Seroprevalence of the polyomaviruses among cases and controls, respectively, was as follows: BKV: 87.5%, 89.4%; JCV 61.7%, 60.3%; MCV 70.6%, 68.8%; HPyV6: 77.1%, 75.0%; HPyV7 60.6%, 61.8%; WUV 97.9%, 99.1%; KIV 94.3%, 95.7%; TSV: 83.9%, 80.3%. There were no case–control differences in median MFI values for any of the polyomaviruses (data not shown). An inverse trend was suggested for TSV antibodies and risk of NHL but the HRs were not statistically significant (Table 1). No other associations were observed for seropositivity or elevated antibody levels of the polyomaviruses and risk of NHL. For the NHL subtypes, the only observed association was between TSV and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (Table 2). Restricted cubic splines did not suggest any nonlinearity in the associations of polyomavirus antibody levels and risk of NHL or NHL subtypes (data not shown).

Table 1.

Associations of polyomavirus serostatus and antibody level with risk of NHL

Median MFIControls (n)Cases (n)ORa (95% CI)
BKV 
 Seronegative  59 35 1.00 (ref.) 
 Seropositive  498 244 0.83 (0.53–1.29) 
  MFI valuesb 
   Q1 615.17 125 62 1.00 (ref.) 
   Q2 2,212.17 124 71 1.15 (0.76–1.76) 
   Q3 5,152.17 125 57 0.91 (0.59–1.42) 
   Q4 9,724.67 124 54 0.88 (0.57–1.36) 
    Ptrend = 0.39 
JCV 
 Seronegative  221 107 1.00 (ref.) 
 Seropositive  336 172 1.07 (0.79–1.45) 
  MFI valuesb 
   Q1 436.19 84 45 1.00 (ref.) 
   Q2 1,133.19 84 48 1.08 (0.64–1.81) 
   Q3 3,199.19 84 41 0.92 (0.55–1.54) 
   Q4 6,620.19 84 38 0.84 (0.49–1.45) 
    Ptrend = 0.81 
WUV 
 Seronegative  1.00 (ref.) 
 Seropositive  552 273 0.42 (0.13–1.37) 
  MFI valuesb 
   Q1 1,924.33 138 77 1.00 (ref.) 
   Q2 4,547.83 138 78 0.99 (0.66–1.47) 
   Q3 6,693.58 138 52 0.66 (0.42–1.01) 
   Q4 1,0049.58 138 66 0.83 (0.55–1.26) 
    Ptrend = 0.23 
KIV 
 Seronegative  24 16 1.00 (ref.) 
 Seropositive  533 263 0.74 (0.39–1.41) 
  MFI valuesb 
   Q1 1,072.42 134 79 1.00 (ref) 
   Q2 2,690.17 133 69 0.86 (0.57–1.31) 
   Q3 4,795.17 133 62 0.79 (0.53–1.18) 
   Q4 8,116.17 133 53 0.66 (0.43–1.02) 
    Ptrend = 0.07 
MCV 
 Seronegative  174 82 1.00 (ref.) 
 Seropositive  383 197 1.09 (0.80–1.49) 
  MFI valuesb 
   Q1 6,35.47 95 50 1.00 (ref.) 
   Q2 4,070.97 96 50 1.01 (0.62–1.65) 
   Q3 6,817.47 96 61 1.24 (0.77–2.01) 
   Q4 9,290.47 96 36 0.72 (0.43–1.20) 
    Ptrend = 0.70 
HPyV6 
 Seronegative  139 64 1.00 (ref.) 
 Seropositive  418 215 1.11 (0.80–1.55) 
  MFI valuesb 
   Q1 1,002.25 105 56 1.00 (ref.) 
   Q2 4,386.25 104 55 0.99 (0.63–1.57) 
   Q3 7,000.75 105 50 0.90 (0.57–1.43) 
   Q4 10,400.00 104 54 0.98 (0.62–1.55) 
    Ptrend = 0.78 
HPyV7 
 Seronegative  213 110 1.00 (ref.) 
 Seropositive  344 169 0.95 (0.71–1.27) 
  MFI valuesb 
   Q1 631.94 86 52 1.00 (ref.) 
   Q2 2,603.19 86 41 0.78 (0.46–1.33) 
   Q3 4,645.44 86 39 0.75 (0.46–1.24) 
   Q4 7,442.44 86 37 0.70 (0.42–1.19) 
    Ptrend = 0.58 
TSV 
 Seronegative  110 45 1.00 (ref.) 
 Seropositive  447 234 1.28 (0.87–1.87) 
  MFI valuesb 
   Q1 1,067.94 111 64 1.00 (ref.) 
   Q2 3,508.94 112 83 1.32 (0.85–2.06) 
   Q3 6,041.94 112 45 0.68 (0.42–1.09) 
   Q4 8,915.69 112 42 0.63 (0.39–1.03) 
    Ptrend = 0.03 
Median MFIControls (n)Cases (n)ORa (95% CI)
BKV 
 Seronegative  59 35 1.00 (ref.) 
 Seropositive  498 244 0.83 (0.53–1.29) 
  MFI valuesb 
   Q1 615.17 125 62 1.00 (ref.) 
   Q2 2,212.17 124 71 1.15 (0.76–1.76) 
   Q3 5,152.17 125 57 0.91 (0.59–1.42) 
   Q4 9,724.67 124 54 0.88 (0.57–1.36) 
    Ptrend = 0.39 
JCV 
 Seronegative  221 107 1.00 (ref.) 
 Seropositive  336 172 1.07 (0.79–1.45) 
  MFI valuesb 
   Q1 436.19 84 45 1.00 (ref.) 
   Q2 1,133.19 84 48 1.08 (0.64–1.81) 
   Q3 3,199.19 84 41 0.92 (0.55–1.54) 
   Q4 6,620.19 84 38 0.84 (0.49–1.45) 
    Ptrend = 0.81 
WUV 
 Seronegative  1.00 (ref.) 
 Seropositive  552 273 0.42 (0.13–1.37) 
  MFI valuesb 
   Q1 1,924.33 138 77 1.00 (ref.) 
   Q2 4,547.83 138 78 0.99 (0.66–1.47) 
   Q3 6,693.58 138 52 0.66 (0.42–1.01) 
   Q4 1,0049.58 138 66 0.83 (0.55–1.26) 
    Ptrend = 0.23 
KIV 
 Seronegative  24 16 1.00 (ref.) 
 Seropositive  533 263 0.74 (0.39–1.41) 
  MFI valuesb 
   Q1 1,072.42 134 79 1.00 (ref) 
   Q2 2,690.17 133 69 0.86 (0.57–1.31) 
   Q3 4,795.17 133 62 0.79 (0.53–1.18) 
   Q4 8,116.17 133 53 0.66 (0.43–1.02) 
    Ptrend = 0.07 
MCV 
 Seronegative  174 82 1.00 (ref.) 
 Seropositive  383 197 1.09 (0.80–1.49) 
  MFI valuesb 
   Q1 6,35.47 95 50 1.00 (ref.) 
   Q2 4,070.97 96 50 1.01 (0.62–1.65) 
   Q3 6,817.47 96 61 1.24 (0.77–2.01) 
   Q4 9,290.47 96 36 0.72 (0.43–1.20) 
    Ptrend = 0.70 
HPyV6 
 Seronegative  139 64 1.00 (ref.) 
 Seropositive  418 215 1.11 (0.80–1.55) 
  MFI valuesb 
   Q1 1,002.25 105 56 1.00 (ref.) 
   Q2 4,386.25 104 55 0.99 (0.63–1.57) 
   Q3 7,000.75 105 50 0.90 (0.57–1.43) 
   Q4 10,400.00 104 54 0.98 (0.62–1.55) 
    Ptrend = 0.78 
HPyV7 
 Seronegative  213 110 1.00 (ref.) 
 Seropositive  344 169 0.95 (0.71–1.27) 
  MFI valuesb 
   Q1 631.94 86 52 1.00 (ref.) 
   Q2 2,603.19 86 41 0.78 (0.46–1.33) 
   Q3 4,645.44 86 39 0.75 (0.46–1.24) 
   Q4 7,442.44 86 37 0.70 (0.42–1.19) 
    Ptrend = 0.58 
TSV 
 Seronegative  110 45 1.00 (ref.) 
 Seropositive  447 234 1.28 (0.87–1.87) 
  MFI valuesb 
   Q1 1,067.94 111 64 1.00 (ref.) 
   Q2 3,508.94 112 83 1.32 (0.85–2.06) 
   Q3 6,041.94 112 45 0.68 (0.42–1.09) 
   Q4 8,915.69 112 42 0.63 (0.39–1.03) 
    Ptrend = 0.03 

aModels using conditional logistic regression to control for the matching factors (age, sex, race, and blood draw date).

bAmong seropositive participants only.

Table 2.

Heterogeneity of the associations of polyomavirus serostatus and antibody levels with risk of NHL subtypes

DLBCLFLCLL/SLLOther NHL
PolyomavirusControlsCasesORa (95% CI)CasesORa (95% CI)CasesORa (95% CI)CasesORa (95% CI)
BKV 
 Seronegative 59 1.00 (ref.) 1.00 (ref.) 1.00 (ref.) 1.00 (ref) 
 Seropositive 498 64 1.86 (0.65–5.32) 41 0.97 (0.37–2.58) 57 0.74 (0.35–1.59) 37 0.49 (0.22–1.12) 
 MFI ≤ 3,463b 249 34 1.00 (ref.) 27 1.00 (ref.) 26 1.00 (ref.) 20 1.00 (ref) 
 MFI > 3,463b 249 30 0.84 (0.49–1.43) 14 0.53 (0.27–1.04) 31 1.21 (0.69–2.10) 17 0.81 (0.41–1.59) 
JCV 
 Seronegative 221 26 1.00 (ref.) 16 1.00 (ref.) 25 1.00 (ref.) 16 1.00 (ref) 
 Seropositive 336 42 1.06 (0.63–1.80) 30 1.20 (0.63–2.26) 41 1.10 (0.64–1.87) 29 1.19 (0.63–2.27) 
 MFI ≤ 1,921b 168 18 1.00 (ref.) 18 1.00 (ref.) 19 1.00 (ref.) 18 1.00 (ref) 
 MFI > 1,921b 168 24 1.32 (0.69–2.54) 12 0.65 (0.30–1.39) 22 1.20 (0.62–2.32) 11 0.60 (0.27–1.32) 
WUVc 
 MFI ≤ 5,813b 276 36 1.00 (ref.) 19 1.00 (ref.) 31 1.00 (ref.) 29 1.00 (ref) 
 MFI > 5,813b 276 31 0.87 (0.52—1.44) 26 1.38 (0.74—2.55) 34 1.07 (0.64—1.79) 16 0.54 (0.28—1.01) 
KIVc 
 MFI ≤ 3,578b 267 36 1.00 (ref.) 26 1.00 (ref.) 32 1.00 (ref.) 25 1.00 (ref) 
 MFI > 3,578b 266 28 0.79 (0.46–1.33) 19 0.71 (0.38–1.32) 28 0.88 (0.51–1.51) 18 0.69 (0.36–1.30) 
MCV 
 Seronegative 174 19 1.00 (ref.) 14 1.00 (ref.) 24 1.00 (ref.) 1.00 (ref) 
 Seropositive 383 49 1.17 (0.67–2.06) 32 1.05 (0.55–2.03) 42 0.80 (0.47–1.37) 37 2.13 (0.97–4.70) 
 MFI ≤ 5,495b 191 19 1.00 (ref.) 17 1.00 (ref.) 23 1.00 (ref.) 24 1.00 (ref) 
 MFI > 5,495b 192 30 1.57 (0.85–2.90) 15 0.85 (0.41–1.77) 19 0.83 (0.44–1.59) 13 0.53 (0.26–1.08) 
HPyV6 
 Seronegative 139 16 1.00 (ref.) 10 1.00 (ref.) 12 1.00 (ref.) 11 1.00 (ref) 
 Seropositive 418 52 1.10 (0.61–2.00) 36 1.19 (0.57–2.47) 54 1.52 (0.79–2.95) 34 1.04 (0.51–2.12) 
 MFI ≤ 5,556b 209 26 1.00 (ref.) 17 1.00 (ref.) 30 1.00 (ref.) 15 1.00 (ref) 
 MFI > 5,556b 209 26 1.00 (0.56–1.79) 19 1.08 (0.54–2.15) 24 0.81 (0.46–1.45) 19 1.22 (0.60–2.49) 
HPyV7 
 Seronegative 213 23 1.00 (ref.) 19 1.00 (ref.) 23 1.00 (ref.) 14 1.00 (ref) 
 Seropositive 344 45 1.21 (0.71–2.08) 27 0.86 (0.46–1.59) 43 1.24 (0.72–2.13) 31 1.41 (0.73–2.75) 
 MFI ≤ 3,540b 172 25 1.00 (ref.) 13 1.00 (ref.) 21 1.00 (ref.) 18 1.00 (ref) 
 MFI > 3,540b 172 20 0.81 (0.43–1.52) 14 1.06 (0.48–2.32) 22 1.02 (0.54–1.93) 13 0.72 (0.34–1.52) 
TSVc 
 MFI ≤ 4,787b 223 33 1.00 (ref.) 21 1.00 (ref.) 38 1.00 (ref.) 21 1.00 (ref) 
 MFI > 4,787b 224 24 0.74 (0.42–1.29) 19 0.94 (0.49–1.80) 19 0.44 (0.24–0.81) 17 0.82 (0.42–1.60) 
DLBCLFLCLL/SLLOther NHL
PolyomavirusControlsCasesORa (95% CI)CasesORa (95% CI)CasesORa (95% CI)CasesORa (95% CI)
BKV 
 Seronegative 59 1.00 (ref.) 1.00 (ref.) 1.00 (ref.) 1.00 (ref) 
 Seropositive 498 64 1.86 (0.65–5.32) 41 0.97 (0.37–2.58) 57 0.74 (0.35–1.59) 37 0.49 (0.22–1.12) 
 MFI ≤ 3,463b 249 34 1.00 (ref.) 27 1.00 (ref.) 26 1.00 (ref.) 20 1.00 (ref) 
 MFI > 3,463b 249 30 0.84 (0.49–1.43) 14 0.53 (0.27–1.04) 31 1.21 (0.69–2.10) 17 0.81 (0.41–1.59) 
JCV 
 Seronegative 221 26 1.00 (ref.) 16 1.00 (ref.) 25 1.00 (ref.) 16 1.00 (ref) 
 Seropositive 336 42 1.06 (0.63–1.80) 30 1.20 (0.63–2.26) 41 1.10 (0.64–1.87) 29 1.19 (0.63–2.27) 
 MFI ≤ 1,921b 168 18 1.00 (ref.) 18 1.00 (ref.) 19 1.00 (ref.) 18 1.00 (ref) 
 MFI > 1,921b 168 24 1.32 (0.69–2.54) 12 0.65 (0.30–1.39) 22 1.20 (0.62–2.32) 11 0.60 (0.27–1.32) 
WUVc 
 MFI ≤ 5,813b 276 36 1.00 (ref.) 19 1.00 (ref.) 31 1.00 (ref.) 29 1.00 (ref) 
 MFI > 5,813b 276 31 0.87 (0.52—1.44) 26 1.38 (0.74—2.55) 34 1.07 (0.64—1.79) 16 0.54 (0.28—1.01) 
KIVc 
 MFI ≤ 3,578b 267 36 1.00 (ref.) 26 1.00 (ref.) 32 1.00 (ref.) 25 1.00 (ref) 
 MFI > 3,578b 266 28 0.79 (0.46–1.33) 19 0.71 (0.38–1.32) 28 0.88 (0.51–1.51) 18 0.69 (0.36–1.30) 
MCV 
 Seronegative 174 19 1.00 (ref.) 14 1.00 (ref.) 24 1.00 (ref.) 1.00 (ref) 
 Seropositive 383 49 1.17 (0.67–2.06) 32 1.05 (0.55–2.03) 42 0.80 (0.47–1.37) 37 2.13 (0.97–4.70) 
 MFI ≤ 5,495b 191 19 1.00 (ref.) 17 1.00 (ref.) 23 1.00 (ref.) 24 1.00 (ref) 
 MFI > 5,495b 192 30 1.57 (0.85–2.90) 15 0.85 (0.41–1.77) 19 0.83 (0.44–1.59) 13 0.53 (0.26–1.08) 
HPyV6 
 Seronegative 139 16 1.00 (ref.) 10 1.00 (ref.) 12 1.00 (ref.) 11 1.00 (ref) 
 Seropositive 418 52 1.10 (0.61–2.00) 36 1.19 (0.57–2.47) 54 1.52 (0.79–2.95) 34 1.04 (0.51–2.12) 
 MFI ≤ 5,556b 209 26 1.00 (ref.) 17 1.00 (ref.) 30 1.00 (ref.) 15 1.00 (ref) 
 MFI > 5,556b 209 26 1.00 (0.56–1.79) 19 1.08 (0.54–2.15) 24 0.81 (0.46–1.45) 19 1.22 (0.60–2.49) 
HPyV7 
 Seronegative 213 23 1.00 (ref.) 19 1.00 (ref.) 23 1.00 (ref.) 14 1.00 (ref) 
 Seropositive 344 45 1.21 (0.71–2.08) 27 0.86 (0.46–1.59) 43 1.24 (0.72–2.13) 31 1.41 (0.73–2.75) 
 MFI ≤ 3,540b 172 25 1.00 (ref.) 13 1.00 (ref.) 21 1.00 (ref.) 18 1.00 (ref) 
 MFI > 3,540b 172 20 0.81 (0.43–1.52) 14 1.06 (0.48–2.32) 22 1.02 (0.54–1.93) 13 0.72 (0.34–1.52) 
TSVc 
 MFI ≤ 4,787b 223 33 1.00 (ref.) 21 1.00 (ref.) 38 1.00 (ref.) 21 1.00 (ref) 
 MFI > 4,787b 224 24 0.74 (0.42–1.29) 19 0.94 (0.49–1.80) 19 0.44 (0.24–0.81) 17 0.82 (0.42–1.60) 

Abbreviations: CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma.

aUnconditional polytomous logistic regression models controlled for the matching factors (age, blood draw date, sex, and race).

bAmong seropositive participants only, median MFI value for each antigen was used as the cutpoint.

cNHL subtype serpositvity analyses were not conducted where there were fewer than 50 seronegative cases.

Results from this prospective study do not support associations between BKV, JCV, WUV, KIV, HPyV6, HPyv7, MCV, and NHL risk. Though an association was observed for TSV and CLL/SLL, and an inverse trend was suggested for TSV and NHL overall (P = 0.03), spline analyses did not detect any linear or nonlinear associations, and chance seems a likely explanation. Three seroepidemiologic studies of human polyomaviruses and NHL risk have been published to date. For BKV, findings from all three were null for all NHL (2, 3) and diffuse large B-cell lymphoma (DLBCL) (4). For JCV, positive (2) and inverse (3) associations have been reported with all NHL as well as a null (4) association with DLBCL. Unlike our findings, one study (4) found a positive association for MCV and DLBCL. The prospective design of our study minimized the potential for reverse causation by the lymphoma or its treatment. However, the NHL subtype results must be interpreted with caution given the sample size limitations. In summary, this study does not support any associations between human polyomaviruses and NHL risk.

No potential conflicts of interest were disclosed.

Conception and design: L.R. Teras, M. Pawlita, S.M. Gapstur

Development of methodology: L.R. Teras, M. Pawlita

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M. Pawlita, A. Michel, M. Willhauck-Fleckenstein, S.M. Gapstur

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): L.R. Teras, D.E. Rollison, M. Pawlita, A. Michel, J.L. Blase, M. Willhauck-Fleckenstein, S.M. Gapstur

Writing, review, and/or revision of the manuscript: L.R. Teras, D.E. Rollison, M. Pawlita, A. Michel, J.L. Blase, M. Willhauck-Fleckenstein, S.M. Gapstur

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): L.R. Teras

Study supervision: S.M. Gapstur

The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research, and would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance, Epidemiology, and End Results program.

The ACS funded the creation, maintenance, and updating of the CPS-II cohort.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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