Risk Factors for Malignant Diseases: A Cohort Study on a ...cebp.aacrjournals.org/content/cebp/6/11/863.full.pdf · Risk Factors for Malignant Diseases: A Cohort Study on a ... Received

Vol. 6, 863-873, November 1997 Cancer Epidemiology, Biomarkers & Prevention 863

Risk Factors for Malignant Diseases: A Cohort Study on a

Population of 22,946 Icelanders

Hrafn Tulinius,’ Nikul#{225}sSigf#{243}sson, Helgi Sigvaldason,Kristin Bjarnad#{243}ttir, and Laufey Tryggvad#{243}ttir

Icelandic Cancer Registry [H. 1., H. S., K. B., L. T.], Faculty of Medicine,

University of Iceland [H. T.]. and Icelandic Heart Association [N. S.], 125

Reykjavlk, Iceland

Abstract

The records of a cohort of 11,580 females and 11,366males participating in an Icelandic cardiovascular riskfactor study were linked with the Icelandic CancerRegistry, identifying 1,785 males and 1,490 females whohad been registered with neoplastic diseases from 1968 to1995. The interval between the time of measurement ofthe variables and the diagnosis of the malignancy rangedfrom 4 to 27 years. The variables consisted of answersfrom a questionnaire on smoking and the use ofhypertensive drugs and anthropometric and biochemical

measurements. Cox’s regression was applied to analyzethe predictive power of the variables on the risk of

cancer after the first examination at the Heart PreventiveClinic, ReykjavIk. Univariate analyses, adjusted for age,were performed for each variable and each major site.Within each major site, multivariate regression analysiswas applied for variables that were found significantly(10% level in umvariate analysis) positive or negative asrisk factors. The results show that smoking is the mostimportant risk factor, negative only for endometrium.For lung cancer, the risk is twice as strong for females asit is for males, whereas for pancreas, males have arelative risk ratio of 4.5, compared with 2.4 for females.Height is a risk factor for all sites for each sex, for breastin females, and for kidney in males. Severalanthropometric risk factors were studied. Some of thesecan describe positive or negative relative risk ratios forcancer, and their use may shed light on cancerpathogenesis. Serum cholesterol is a negative risk factorfor breast cancer in females, but triglycerides are apositive risk factor for cervix cancer in females and forcolon or rectum and thyroid cancer in males. Serumglucose is a positive risk factor for prostate cancer and anegative risk factor for lymphomas and leukemias.

Introduction

Malignant diseases have latency periods, the time lag between

the initial carcinogenic action and the point in time when the

Received I 2/1 3/96; revised 7/17/97; accepted 7/29/97.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 inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.t To whom requests for reprints should be addressed, at the Icelandic Cancer

Registry, P. 0. Box 5420, 125 Reykjavfk. Iceland.

malignancy has reached a mass making its diagnosis possible.

Most of our knowledge on carcinogenesis is derived from

laboratory and animal experimentation and epidemiological

studies. Laboratory and animal experimentation investigations

endeavor to test whether a particular chemical or physical agent

leads to cancerous processes in cells or animals. Epidemiolog-

ical studies involve examining groups of people to determine

whether certain exposures alter the risk for particular diseases.

The results of epidemiological studies are often given in the

form of hazard ratios or risk factors. A positive risk factor is a

characteristic that is more common in a group of people who

have or will develop disease than it is in other people.

The purpose of this study was to test hypotheses on asso-

ciations between previously reported risk factors and neoplastic

diseases in a population-based cohort. This was done by record

linkage, facilitated by unique person identification numbers,

between two population-based files, one a prospective study of

risk factors for cardiovascular diseases, The ReykjavI’k Study

(1, 2), and the other a population-based cancer registry, the

Icelandic Cancer Registry (3). The ReykjavIk Study contributed

smoking information and other items from a questionnaire and

standardized anthropometric, biochemical, and blood pressure

measurements and the Cancer Registry provided information

on cancer diagnoses, exact locations of neoplasms, and practi-

cally complete follow-ups for cancer. Both the ReykjavIk Study

and the Cancer Registry had information on date of death or

emigration, if applicable. There have been two previous pub-

lications on record linkage between these files (4, 5).

The hypotheses to be tested included the following: car-

cinogenic effect of smoking differs between males and females;

weight, height, and other anthropometric variables are signill-

cant risk factors for cancer; and cholesterol is a negative risk

factor and triglycerides are a positive risk factor for cancer. The

first hypothesis refers to several publications (6-13) reporting

stronger carcinogenic activity of smoking in females than in

males. A contrary view has also been reported (14). The pos-

sibility was considered that this and the negative risk of smok-

ing for endometrial cancer is mediated by the effect of smoking

on hormonal balance ( 15-25). Our previous publications found

that height was a positive risk factor for certain sites and that

both height and weight were risk factors for breast cancer (4, 5),

and numerous studies have been published on similar hypoth-

eses (26-33). If height is a positive risk factor for a neoplastic

disease, this would suggest that the first two decades of life are

of importance for that carcinogenic process, and questions need

to be answered about how much and how early do people lose

weight as a result of the disease prior to its diagnosis. Triglyc-

erides are, like smoking, candidates for being simultaneously

risk factors for cancer and cardiovascular diseases, but choles-

terol is a negative risk factor for cancer and a positive one for

cardiovascular disease. Some studies have concluded that this

should be regarded as an effect of the disease (34-36).

on May 6, 2018. © 1997 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from

http://cebp.aacrjournals.org/

B

M 2954w 3101Participants

Stage I

Stage II

Stage III

Stage IV

Stage V

TOTAL GROUP OF MEN - 12.843

864 RIsk Factorsfor Malignant Diseases

C A D E

I M 2743 I I M 2756 I I M 2283 I I M 2106 I

_________ I w 2�pJ [��2936 I ] W 2429 11 w 2191

M1970-’71 I __M 1967-68 _________w 1968-’69

M1974-’76 � ____w 1977-’79 Ehw 1971-’72

M 1979-81 _________� H I II

w 1981-’84 ________ ________M 1985-’87 _________ _________

W1987-’91 � � �1L H___TOTAL GROUP OF WOMEN � 13.647

Materials and Methods

The Cardiovascular Risk Factor Study. The Icelandic studyof risk factors for cardiovascular diseases, often called theReykjavIk Study, was started in 1967 (1). People invited to

participate in the Reykjavfk Study were all legal residents of themetropolitan ReykjavIk area on December 1, 1966. The menwere born in 1907, 1910, 1912, 1914, 1916, 1917, 1918, 1919,

1920, 1921, 1922, 1924, 1926, 1928, 1931, and 1934, and the

women were born 1 year after each of these years, i.e. , in 1908,191 1, and so on. Both sexes were divided into groups A, B, and

C according to the day of birth as follows: those in group Bwere born on days 1 , 4, 7, and so on, of each month; those ingroup C were born on days 2, 5, 8, and so on, of each month;

and those in group A were born on days 3, 6, 9, and so on, ofeach month. Groups D and E was comprised of people born inthe years previously left out in the period from 1907 to 1935.The study was performed in five stages: the first took place in

1967-1969, the second in 1970-1972, the third in 1974-1979,

the fourth in 1979-1984, and the fifth in 1985-1991. Group Bwas invited to participate in all five stages of the study, group

C in stages 2 and 3, group A in stage 3, group D in stage 4, andgroup E in stage 5 (Fig. 1). This population numbered 26,490.Cohorts of people from other areas of Iceland, together withpeople born in other years, were added later: a rural population

(born 1907-1936) numbering 2257 persons and a cohort ofyoung people (born 1940-1954) numbering 2781. This studyused only data from each person’s first visit. The mean re-sponse rate was approximately 73%. At the clinic visit a thor-

ough questionnaire concerning various risk factors for cardio-vascular diseases, including smoking, was followed by a series

of anthropometric and biochemical measurements (2). Eachvisit was concluded by a physical examination by a doctor.

The Icelandic Cancer Registry. The Icelandic Cancer Reg-istry was started by the Icelandic Cancer Society in 1954 and

has been operated by that society since (3). It covers the entirepopulation of Iceland and determines incidence of cancer bysite. The registry receives information from all pathology andcytology laboratories in the country, as well as from hospitals,general practitioners, specialists, and individual health workers.Complete follow-up of the study population, as well as popu-lation-based cancer registration, is much facilitated by TheIcelandic National Roster, which has been in operation since1952. In this roster, every member of the population has a

unique identification number, which is used by the Cancer

Fig. I. The ReykjavIk Study: sche-

matic figure of the study plan of theReykjavfk Study, including number ofparticipants, divided into study groups,

and the time of invitation of each study

group to examination in the five stages,

from stage 1 (in 1968) to the stage 5 (in1986). The invited population was di-vided into groups and labeled A to E.

The numbers shown represent the num-

ber of persons originally selected into

each group.

Table 1 Number of cases by can cer site

Cancer sites ICD-7 Males Females Total

Esophagus 150 34 15 49

Stomach 151 171 75 246

Colon and rectum 153-154 193 145 338

Pancreas 157 65 36 101

Lungs 162 273 199 472

Breast 170 439 439

Cervix 171 40 40

Endometrium 172 98 98

Ovary 175 86 86

Prostate 177 524 524

Kidney 180 109 58 167

Urinary bladder 181 167 48 215

Brain 193 40 59 99

Thyroid gland 194 37 46 83

Lymphoma 200-202 45 33 78

Myeloma 203 2 1 23 44

Leukemia 204 33 26 59

All sites 140-205 1785 1490 3275

Registry for linkages with the study population. Of the popu-lation attending, 0.6% were lost to follow-up due to emigration

during the study period, and around 94.5% of diagnosed caseshad histological confirmation. The main purpose of this registryis epidemiological research.

The Approach. There have been two previous publications onthis record linkage (4, 5), covering cancer incidence until 1983.This paper updates the record linkage to 1995, making the totalnumber of individuals with neoplastic diseases 3275, as shown

in Table 1.The material from the Cancer Registry consists of in-

formation on those initially cancer-free members of theReykjavIk Study cohort who had been registered in theIcelandic Cancer Registry with a malignancy diagnosed afterthe person’s first visit to the cardiovascular clinic. Theresults of anthropometric measurements, blood pressure,

biochemistry, and smoking status, all from the first visit tothe cardiovascular study clinic, constitute the information

used in this investigation. Table 2 shows the mean valuesand SDs of the variables measured on the first visit to the

ReykjavIk Study clinic. The total number of persons in thecohort is 22,946, 1 1 ,580 females and 1 1 ,366 males. Of these,



Cancer Epidemiology, Biomarkers & Prevention 865

Table 2 Characteristic s of potential risk factors

.Risk factors

No. of persons (total no., 22,946)

Males (total Females (total

no., 11,366) no., 11,580)

Mean SD Mean SD

Calendar year 1974.8 6 1976.1 6.4

Age (yr) 50.3 1 1 50.5 1 1.2

Height (cm) 176.8 6.4 163.5 5.8

Weight (kg) 79.8 12 66.7 11.8

Cholesterol (nimol/liter) 6.29 1 . 1 1 6.48 1.27

Triglycerides (mmollliter) 1.22 0.7 1.04 0.54

Glucose, fasting (mmollliter) 4.55 0.78 4.33 0.72

Glucose, 90 mm (mmollliter) 5.61 1.94 5.83 1.72

Creatinine (p�mo1Jliter) 91.9 15 77.8 28.3

Uric acid (mmollliter) 0.32 0.07 0.26 0.06

Lean body mass (kg) 62.6 6.2 48 4.8

Body surface (m2) 1.96 0.16 1.71 0.15

Body fat (kg) 27.3 13.6 38.8 17.7

BMI (kg/rn2) 25.5 3.5 24.9 4.3

Systolic bpa (��{g) 140 19 136 21

Diastolic bp (mmHg) 87 1 1 83 10

Antihypertensive drugs (%) 6 10

Hypertension (%) 5 24

Smoking, never (%) 22 44

Smoking, former (%) 24 15

Smoking, pipe/cigar (%) 24 2

Smoking, 1-14 cigarettes/day (%) 1 1 20

Smoking, 15-24 cigarettes/day (%) 13 16

Smoking, 25+ cigarettes/day (%) 6 3

‘� bp, blood pressure.

1785 males and 1490 females have been registered with one or

more malignant disease in the cancer registry. Because someindividuals are diagnosed with more than one cancer, the total

number of malignant neoplasms is 1935 in males and 1583 infemales, with second primary cancers at same site excluded. The

follow-up period ranges from 4 to 27 years, and follow-up was

performed from 1968 to 1995.

Table 1 shows the number of cases for those cancer siteswhere the numbers were deemed sufficient for meaningful

calculations. Table 2 gives the mean value, SD, and units usedfor measured variables and percentages for variables with yes

or no answers.

Statistical Methods. Cox’s regression was applied to ana-lyze the predictive power of various variables on the mci-dence of the first cancer (total or site specific) after theexamination at the Heart Preventive Clinic. Univariate anal-

ysis for each variable in males and females was performed.The variable, age, was always included for controlling for its

confounding effect. As many of the variables are highly

correlated, multivariate regression was applied, includingthe variables that were significant at a 10% level in univa-nate analysis. Those variables not showing independent sig-nificance at a 5% level in the multivariate analysis were notreported.

In the stepwise analysis, the inclusion of a variable de-pends on the change in the likelihood ratio (f test). When tworelated variables (e.g., weight and BMI2) both contributed sig-nificantly in the absence of the other, the one causing greatestchange in likelihood ratio was chosen.

2 The abbreviations used are: BMI, body mass index; RR, relative risk; CI,

confidence interval.

To look for differences in anthropometric risk factors

between pre- and postmenopausal breast cancer patients, uni-variate analysis was performed separately for women under 55

years of age and those 55 years and older.Formulas for calculating anthropometric variables and

definition of hypertension are given in the Appendix.

Results

Results of the univariate tests are given in Tables 3-6, andresults of the multivariate regression are given in Tables 7 and

8. Table 3 shows the results of Cox’s regression of the RRs,adjusted for age, for categories of smoking relative to neversmokers for sites where P was less than 0. 10. The same infor-mation is given in Tables 4, 5, and 6 for anthropometricvariables, serum biochemical results, and blood pressure,

respectively.Stepwise multiple regression tests were performed for

those combinations of variable and sites for which univariatetests had shown significant risk. Age was always included butwas not listed in the final conclusion. In Tables 7 and 8, onlyvariables showing Ps of less than 0.05 are included.

Table 9 gives the results for breast cancer risk by anthro-pometric variables for women younger than 55 years old and

those 55 years and older.Table 10 gives the results dividing the groups of patients

into those diagnosed with cancer within 10 years from meas-urement and those diagnosed more than 10 years after meas-

urement.

Smoking. Smoking in all smoking categories is a significantrisk factor for lung cancer in both sexes. In the highest

smoking category, smoking more than 24 cigarettes a day,the risk is 39.7 (95% CI, 18.5-80.8) for females and 27.3(95% CI, 14.2-52.4) for males, after adjustment for other

significant risk factors. Cigarette and cigar smoking remainsa significant risk factor for pancreas cancer in males. Smok-ing more than 24 cigarettes a day is a significant risk factor

for pancreas cancer for females, after adjustment for age

only (RR, 4.52; 95% CI, 1.02-20.1), but when adjusted forother risk factors, it is not significant (RR, 4.44; 95% CI,0.99-19.8). For the cervix, smoking is significant risk factorat less than 25 cigarettes a day. For endometrium, smokingis a negative risk factor, significant only for smoking less

than 15 cigarettes a day. Smoking is a risk factor for urinarybladder in males, significant in all smoking categories exceptsmoking less than 15 cigarettes a day, but in females, it is nota significant risk factor for urinary bladder.

Anthropometric Variables. Height is a significant positive

risk factor for kidney, for all sites in males, after adjustment

for smoking, and for breast in females, after adjustmentfor cholesterol. In women younger than 55 years, the unad-

justed hazard ratio for breast is 1.037 (P = 0.058), and inwomen 55 years and older, it is 1.025 (P 0.012), as seen

in Table 9.After adjustment for other risk factors, weight is a

significant positive risk factor for kidney in females, but notfor any site for males. It is a significant negative risk factor

for urinary bladder for females. When adjusted for age only,weight is also a positive risk factor for breast, endometrium,brain, and thyroid in females, and a significant negative riskfactor for stomach and lung for males and for esophagus and

lung for females. For women 55 years and older, the hazardratio for breast cancer, adjusted for age only, is significant(1.012; P = 0.006).

After adjustment for other risk factors, BMI is a significant



866 Risk Factors for Malignant Diseases

Table 3 RRs relative to never smokers

Smoking categories

Site Former smoker Pipe Cigars 1-14 cigarettes/thy 15-24 cigarettes/day 25+ cigarettes/day

RR 95% CI RR 95% CI RR 95% CI RR 95% CI RR 95% CI RR 95% CI

Males

Esophagus 2.04 0.63-6.64 2.03 0.51-8.14 1.6 0.36-7.21 3.6 1.01-12.8 4.1 1.19-14.1 1.46 0.16-13.2

Stomach 1.17 0.75-1.84 1.28 0.75-2.18 1.05 0.59-1.89 1.45 0.84-2.50 1.87 1.13-3.09 0.99 0.41-2.35

Pancreas 2.37 0.74-7.56 2.52 0.68-9.39 4.87 1.49-15.9 7.18 2.31-22.3 10.2 3.43-30.6 12.5 3.73-41.7

Lung 2.91 1.47-5.74 11.1 5.86-21.2 4.05 1.95-8.40 6.49 3.25-13.0 13.5 7.08-25.6 28.7 14.9-55.1

Urinary bladder 2.31 1.37-3.90 2.56 1.43-4.59 2.14 1.16-3.96 1.49 0.74-2.99 2.59 1.42-4.74 4.6 2.37-6.91

Brain 1.48 0.53-4.16 1.26 0.36-4.46 1.89 0.61-5.87 1.44 0.41-5.1 1 2.67 0.92-7.73 2.5 0.62-10.0

All sites 1.2 l.�-l.39 1.58 1.34-1.86 1.28 1.07-1.53 1.51 1.26-1.79 1.88 1.60-2.22 2.32 1.89-2.85

Females Pi� or Cigars

Colon and rectum 1.07 0.65 -1.77 0.31 0.04 -2.25 1.28 0.84 -1.95 1.42 0.89 -2.29 2.33 0.93 -5.83

Pancreas 0.91 0.30 -2.76 1.35 0.18 -10.3 1.52 0.66 -3.52 1.69 0.� -4.43 4.52 1.02 -20.1

Lung 3.73 1.73 -8.07 15.7 6.78 -36.3 9.39 4.99 -17.7 30.7 16.8 -56.0 44.1 21.1 -91.8

Cervix 1.16 0.37 -3.64 2.79 1.26 -6.15 2.68 1.14 -6.34 1.84 0.24 -14.3

Endometrium 0.71 0.39 -1.29 0.32 0.04 -2.31 0.49 0.27 -0.88 0.49 0.24 -0.99 0.83 0.20 -3.40

Leukemia 2.08 0.68 -6.35 1.14 0.34 -3.78 3.96 1.52 -10.3

All sites 1.07 0.91 -1.26 1.05 0.74 -1.50 1.32 1.15 -1.51 1.75 1.52 -2.02 2.55 1.94 -3.36

Results of univariate Cox’s regression, adjusted for age.

Table 4 Univariate RRs for anthropometric variables

Variables

Site Height (m) Weight (kg) BMI (kg/m2) Bodys�irface B�y fat (kg) Lean body mass (kg)

RR 95%CI RR 95%CI RR 95%CI RR 95%CI RR 95%CI RR 95% CI

Males

Esophagus 0.97 0.937-0.999

Stomach 0.98 0.967-0.994 0.935 0.892-0.980 0.22 0.08-0.59 0.99 0.974-1.000

Colon and rectum 1.01 0.999-1.022 1.037 0.995-1.080 2.21 0.88-5.54 1.01 1.001-1.020

Pancreas I .035 0.994-1.078

Lung 0.976 0.965-0.986 0.899 0.865-0.934 0.28 0.13-0.62 0.98 0.968-0.989

Prostate 1 .014 0.999-1 .029 1 .006 0.999-1 .014 1.64 0.93-2.89

Kidney 1.048 1.016-1.082 1.014 0.998-1.030 3.59 1.06-12.1 1.03 1.002-1.065

Thyroid 1.1 1.009-1.199

Leukemia 1.024 0.996-1.052 1.092 0.994-1.199

All sites 1.01 1.003-1.018 0.987 0.973-1.001

Females

Esophagus 0.938 0.889-0.990 0.824 0.707-0.962 0.02 0.00-0.64 0.97 0.935-1.004

Stomach 0.95 0.901-0.996

Pancreas 1.055 0.993-1.120 1.08 1.014-1.150

Lung 0.958 0.944-0.971 0.875 0.840-0.91 1 0.07 0.02-0.18 0.98 0.968-0.986 0.96 0.926-0.985

Breast 1.029 1.012-1.047 1.01 1.002-1.018 2.73 1.46-5.13 1.03 1.010-1.053

Cervix 0.945 0.893-1.001 0.07 0.01-0.67 0.93 0.868-0.999

Endometrium 1.023 1.008-1.038 1.056 1.013-1,100 7.68 2.19-28.2 1.02 1.008-1.029 1.04 1.002-1.086

Kidney I .027 1 .008-1 .046 1 .076 1 .024-1 . 1 30 7.26 1.36-38.6

Urinary bladder 0.968 0.941-0.995 0.915 0.847-0.989 0.15 0.02-1.1 1 0.98 0.964-1.000 0.95 0.890-1.009

Brain 1.029 1.01 1-1.047 1.069 1.016-1.125 14.3 2.9-70.7 1.01 1.000-1.028 1.06 1.008-1.117

Thyroid 1.024 1.002-1.046 1.068 1.008-1.132 6.56 1.02-42.4 1.02 1.005-1.036

All sites 1.01 1.001-1.020 1.01 0.999-1.021


negative risk factor for lung in both sexes and for esophagus infemales. When adjusted for age only, BMI is a positive risk

factor for thyroid in males and for endometrium, kidney, brain,and thyroid for females, and a negative risk factor for stomachin males and for urinary bladder in females.

After adjustment for other risk factors, body surface is

a significant positive risk factor for brain in females and anegative risk factor for stomach in males and for cervix infemales. When adjusted for age only, body surface is also a

positive risk factor for kidney in males and breast, endome-trium, kidney, brain, and thyroid in females, and a negativerisk factor for lung in males and for esophagus and lung in

females. In women 55 years and older, the unadjusted hazardratio for breast is significant, 2.84 (P = 0.004), slightlyhigher than that for all women, 2.73.

Body fat is a significant positive risk factor for endome-trium in females and a negative risk factor for esophagus in

males. When adjusted for age only, body fat is also a significant




Table 5 Univariate RRs for blood serum measurements

Variables

Site Cholesterol Triglycerides Glucose fasting Glucose, 90 mm(mmol/liter) (mmollliter) (mmol/liter) (mmol/liter)

Creatinine

(�mol/liter)

Uric acid

(mmol/liter)

RE 95%CI RE 95%CI RR 95%CI RR 95%CI RR 95%CI RR 95% CI

Males

Stomach 0.7 0.52-0.95 0.91 0.83-1.00 0.1 1 0.01-1.35

Colon and rectum 1.12 0.96-1.27 1.24 1.05-1.47

Lung 0.91 0.84-0.98 0.98 0.968-0.987

Prostate 1.11 1.01-1.22

Urinary bladder 1.15 1.00-1.33 0.99 0.975-0.999 0.06 0.00-0.80

Brain 1.32 0.97-1.80

Thyroid 1.46 1.12-1.91 1.01 0.999-1.011

All sites 1 .05 1 .00-1 . 12 1 0.993-1.000

Females

Colon and rectum 1.1 1 0.98-1.26 1.29 1.01-1.65 1.06 0.99-1.13

Pancreas 1.43 0.95-2.14 1200 16-92,000

Lung 0.73 0.56-0.96 0.91 0.83-1.00 0.98 0.963-0.988 0.07 0.01-0.83

Breast 0.9 0.83-0.98

Cervix 1.51 1.01-2.25

Endometrium 1.31 0.97-1.77 1.07 1.00-1.14

Urinary bladder I .42 1 .00-2.01 1 .08 1.00-1.17

Brain 1.21 0.97-1.52 300 6-15,500

Thyroid 1.12 1.06-1.19 1 1.001-1.003

Lymphoma 0.76 0.55-1.04 0.47 0.25-0.89 0.77 0.59-1.01

Myeloma 0.73 0.49-1 .43 0.93 0.901-0.969

Leukemia 0.44 0.22-0.90 0.68 0.49-0.93

All sites 0.95 0.91-0.99 1 . 14 1 .04-1 .24 1 1.000-1 .002 2.44 1.02-5.79


Table 6 Univariate RRs for blood pressure measurements

Variables

Sites Systolic bpa (��g) Diastolic bp (mmHg)

RE 95%CI RR 95%CI RR

Hypertension

95%CI

Hypertensive drugs

RR 95% Cl

Males

Esophagus 0.98 0.960-1.000

Lung 0.992 0.984-1.000 0.7 0.5-1.0 0.5 0.2-1.0

Prostate 1.009 1.001-1.017 1.2 1.0-1.4 1.4 1.0-1.9

Kidney 1.009 0.999-1.018 1.017 1.000-1.034

Thyroid 4 1.7-9.6

Lymphoma 1.8 1.0-3.3

All sites 1.2 1.0-1.5

Females

Pancreas 2.3 1.2-4.5 2.1 0.9-4.8

Lung 0.989 0.981-0.996 0.965 0.951-0.980 0.7 0.5-0.9 0.5 0.3-0.9

Endometrium 1.016 1.007-1.024 1.028 1.010-1.045 1.9 1.2-2.9

Kidney 1 .01 3 1 .002-1 .025 1 .029 1 .007-1 .052 2 1.0-4.1

Urinary bladder 0.976 0.948-1.005

Brain 1.024 1.001-1.047

Thyroid I .037 1.012-1.062

Results of univariate Cox’s regression, adjusted for age.a bp, blood pressure.

positive risk factor for colon and rectum in males and brain and

thyroid in females.Lean body mass is a significant positive risk factor for

pancreas in females and a negative risk factor for stomach infemales. When adjusted for age only, lean body mass is also a

significant positive risk factor for kidney in males and for

pancreas in females, a positive risk factor for breast, endome-trium, and brain in females, and a negative risk factor forstomach, lung, and cervix in females.

To look for differences in anthropometric risk factors

between pre- and postmenopausal breast cancer patients, thehazard ratios for women younger than 55 and women 55 yearsand older were determined and are shown in Table 9. In the

younger group, ratios were found not to be significant forheight, weight, body fat, or body surface; the lowest P is for

height, 0.058, and the hazard ratio is 1.037. For the older group,height, weight, and body surface are significant, but body fat is

not (P = 0. 15; hazard ratio, 1.00). The hazard ratios are 2.84 for



Table 7 Multivariate RRs for smoking

Site Smoking status” RR 95% CI

Males

Pancreas

Table 7 Continued

Site Smoking status’� RR 95% CI

Females

All sites Former

Pipe and cigar

l-l4cigarettes/day

15-24 cigarettes/day

25+ cigarettes/day

Cholesterol (mmol/liter)

Triglycerides (mmol/liter)

Creatinine (�.smol/liter)

1.06

1 .02

1.32

1 .74

2.43

0.94

1.12

I .001

0.90-1.25

0.72-1.47

1.16-1.51

1.51-2.00

1.84-3.20

0.89-0.98

1.03-1.23

1.000-1.002

2.37

2.52

4.87

7.18

10.2

12.5

3.03

10.2

4.16

6.02

I 2.0

27.3

0.932

0.986

2.31

2.56

2.14

I .49

2.59

4.60

1.19

1.57

1.28

I .52

1.90

2.32

1.012

Results of Cox’s regression, adjusted for age.a Smoking status RRs are relative to never smokers.

0.74-7.56

0.68-7.39

1.49-15.9

2.31-22.3

3.43-30.6

3.73-41.7

1.54-5.98

5.38-19.5

2.00-8.63

3.01-12.0

6.31-22.9

14.2-52.4

0.899-0.967

0.977-0.996

1.37-3.90

1.43-4.59

1.16-3.96

0.74-2.99

1.42-4.74

2.37-8.91

1.03-1.38

1.33-1.85

1.08-1.53

1.28-1.81

I .61-2.23

1.88-2.85

1.004-1.020

1.12 0.68-1.86

1.37

1.53

2.48

I .07

0.89

I .39

I .71

1.93

4.44

1.075

870

3.69

14.7

8.17

26.3

38.7

0.926

0.984

1.23

0.90-2.08

0.95-2.46

0.99-6.19

1.00-1.13

0.29-2.72

0. 18-10.6

0.74-3.98

0.73-5.10

0.99-19.8

1.009-1.146

10-73,000

1.71-7.99

6.35-34.1

4.33-15.4

14.4-48.1

18.5-80.8

0.891-0.963

0.971-0.996

0.39-3.86

Blood Serum Measurements. After adjustment for other risk

factors, cholesterol is a significant negative risk factor for

breast and all sites in females. When adjusted for age only,cholesterol is not a significant risk factor for other sites.

After adjustment for other risk factors, triglycerides are a

significant positive risk factor for colon and rectum and thyroidin males and for cervix in females. When adjusted for age only,triglycerides are a positive risk factor for colon and rectum and

urinary bladder in females and a negative risk factor for stom-ach in males. Triglycerides are a significant positive risk factorfor colon and rectum and for thyroid cancer in males and forendometrium in females, in the group diagnosed within 10

years of measurement, but not for any site in the group ofpatients diagnosed more than 10 years after measurement, as

seen in Table 10.After adjustment for other risk factors, fasting glucose is a

significant positive risk factor for prostate in males and anegative risk factor for lymphoma in females. When adjustedfor age only, fasting glucose is also a positive risk factor for

urinary bladder and all sites for males and a significant negativerisk factor for lung, lymphoma, and leukemia for females.

After adjustment for other risk factors, glucose, 90 mmafter consumption, is a significant positive risk factor for colonand rectum in females and a significant negative risk factor forleukemia in females. When adjusted for age only, it is a sig-

nificant positive risk factor for endometrium, urinary bladder,and thyroid in females, and it is a significant negative risk factor

for lung in males and for leukemia in females.After adjustment for other risk factors, creatinine is a

significant positive risk factor for thyroid in females and a

significant negative risk factor for lung in both sexes and formyeloma for females. Adjusting for age only, it is also a

2.55 1.15-5.67 significant negative risk factor for urinary bladder in males.2.45 1.03-5.82 After adjustment for other risk factors, uric acid remained1.65 0.21-12.9 a significant positive risk factor for pancreas in females, but0.08 0.01-0.76 after adjustment for age only, it is also a significant positive risk1 .55 1 .09-2.39 factor for brain and all sites in females and a significant neg-0.72 0.40-1.32 ative risk factor for urinary bladder in males and for lung in0.33 0.05-2.40 females.0.53 0.29-0.96

0.54 0.27-1. 10 Blood Pressure. Systolic blood pressure did not remain sig-0.91 0.22-3.75 nificant after adjustment for other risk factors, but after adjust-1.016 1.005-1.027 ment for age only, females have a statistically significant pos-

itive risk for endometrium and for kidney and a significant

negative risk for lung.After adjustment for other risk factors, diastolic blood

pressure is a significant positive risk factor for thyroid infemales, but after adjustment for age only, it is a significant

positive risk factor for prostate and kidney in males and for

body surface (P 0.004), 1.025 for height (P = 0.012), andI .012 for weight (P = 0.006). Height is not a significantnegative risk factor for any site.


Former

Pipe

Cigar

1-14 cigarettes/day

I 5-24 cigarettes/day

25 + cigarettes/day

Lung Former

Pipe

Cigars

1-14 cigarettes/day


25 + cigarettes/day

BMI (kg/rn2)

Creatinine �rnoMiter

Urinary bladder Former

Pipe

Cigars

1-14 cigarettes/day

1 5-24 cigarettes/day

25 + cigarettes/day

All sites Former

Pipe

Cigar

I -I 4 cigarettes/day


25 + cigarettes/day

Height (m)

Females

Colon and rectum Former

Pipe and cigar

I -14 cigarettes/day


25 + cigarettes/day

Glucose 90 mm (rnmollliter)

Pancreas Former

Pipe and cigar

1-14 cigarettes/day

1 5-24 cigarettes/day

25 + cigarettes/day

Lean body mass, (kg)

Uric acid (rnrnol/liter)

Lung Former

Pipe and cigar

1-14 cigarettes/day

I 5-24 cigarettes/day

25 + cigarettes/day

BMI (kg/rn2)

Creatinine (�.smol/liter)

Cervix Former

Pipe and cigar

1-14 cigarettes/day


25 + cigarettes/day

Body surface (rn2)

Triglycerides (mrnol/liter)

Endornetriurn Former

Pipe and cigar

1-14 cigarettes/day


25+ cigarettes/day

Body fat (kg)




Table 8 Multivariate RRs for anthropometric variables, serum measurements,

and blood pressurea

Results of Cox’s regression, adjusted for age.

Variable Site RR 95% CI

Height (m) Males

Kidney 1.048 1.046-1.082

Females

Breast 1.027 1.010-1.045

Cholesterol mmol/l 0.91 0.84-0.99

Weight (kg) Females

Kidney I .027 1.008-1.046

Urinary bladder 0.968 0.941-0.995

BMI (Kg/rn2) Females

Esophagus 0.924 0.707-0.962

Body surface (m2) Males

Stomach 0.22 0.06-0.59

Females

Brain 14.3 2.9-70.7

Body fat (kg) Males

Esophagus 0.967 0.937-0.999

Lean body mass (kg) Females

Stomach 0.947 0.901-0.996

Triglycerides mmolIl Males

Colon and rectum 1.24 1.05-1.47

Thyroid 1.42 1.00-1.84

Hypertensive drugs 3.6 1.5-8.6

Glucose fasting (mmol/liter) Males

Prostate 1.11 1.01-1.22

Females

Lymphoma 0.47 0.25-0.89

Glucose at 90 mm (mmol/liter) Females

Leukemia 0.68 0.49-0.93

Creatinine (�amol/liter) Females

Thyroid 1.002 1.001-1.003

Diastolic bpb (mmHg) I .038 1.013-1.064

Myeloma 0.932 0.901-0.969

a See also Table 7.

b bp, blood pressure.

endometrium, brain, and thyroid in females and a significantnegative risk factor for lung in females.

Hypertension did not remain significant after adjustmentfor other risk factors, but alter adjustment for age only, it is a

significant risk factor for prostate and lymphoma in males and

for pancreas and endometrium in females, as well as a signif-icant negative risk factor for lung in females.

After adjustment for other risk factors, taking hypertensivedrugs remains a significant positive risk factor for thyroid in

males, but after adjustment for age only, it is a significantpositive risk factor for prostate and all sites in males and forkidney in females and a significant negative risk factor for lungin females.

Discussion

This study has certain limitations. The information on riskfactors is entirely based on the subjects’ first visits to the

Reykjavfk Study Clinic. The information consists of measure-ments, anthropometric and biochemical, and questionnaire re-plies. Care has been taken to introduce quality control in the

measurements (2) whenever feasible. The questionnaire wasfilled in by the participant, who brought it to the clinic and

discussed it with a health worker. Because this is informationobtained at one point in time, nothing can be said about itemssuch as lifetime smoking or weight changes by age. Another

Table 9 Breast cancer incidence for 91 women under 55 years of age and

343 women 55 years and older

Univariate RRs for anthropometric variables (96% CI). Results of Cox’s regres-

sion, adjusted for age.

VariableUnder 5 years 55 years and older

Hazard ratio 96% CI Hazard ratio 96% CI

Height (cm) 1.036 0.998-1.076 1.025 1.005-1.045

Weight (kg) 0.995 0.977-1.014 1.012 1.003-1.020

BMI (kg/m2) 1.009 0.965-1.055 1.023 0.999-1.048

Body surface (m2) 1.35 0.32-5.66 2.78 1.37-5.65

Body fat (kg) 1 .001 0.988-1 .014 1 .004 0.998-1.010

Lean body mass (kg) 1 .009 0.965-1 .055 1 .032 1.009-1.054

limitation is that the size and age composition of the study

cohort limits the possibilities of analysis.The strengths of the investigation are the complete fol-

low-up of the cohort and the availability of uniform informationon smoking and anthropometric and biochemical measure-ments, which can be evaluated simultaneously.

Smoking. The strongest and most important individual risk

factor is smoking. As seen in Table 3, any category of smokingis a significant risk factor for lungs in both sexes and for all sitesin males. Adjusting for other significant risk factors did not

change these risks markedly, as seen in Tables 7 and 8. Pan-

creas in males had a significantly increased risk for all cigarettesmoking categories and for cigars, but for females, for the

category of smoking more than 25 cigarettes per day, the risk

factor becomes insignificant after adjustment for lean bodymass and uric acid. Urinary bladder is significantly positive in

all but one (1-14 cigarettes per day) category in males, but it is

not significant in females.Several papers have addressed the question whether there

is a gender difference in the carcinogenic effect of smoking,

indicating a greater risk for women. Some have concluded in

favor of such a difference (6-13), but others (14) have doubtedthe evidence. An earlier paper had shown higher risk in womenfor certain histology types of lung cancer (15). To test whetherin this material evidence can be found for this gender differ-

ence, individual smoking categories were compared betweenthe sexes. For lung, the risks are higher in every category forfemales, significant only for smoking 15-24 cigarettes per day,for which females have a risk of 30.7 (95% CI, 16.8-56.0) and

males have a risk of 13.5 (95% CI, 7.08-25.6; see Table 3).

This is in support of a greater susceptibility to carcinogeniceffects of smoking for lung cancer. It is possible that misclas-

sification bias could be at work, but only if one assumes thatmales overstate their quantity of smoking and/or that women

under-report their smoking. Evidence for such a bias is difficultto find. Biological support has been advanced (12) in suggest-ing differences in detoxification mechanisms involving thecytochrome P-450 enzymes and difference in activity of sexhormones. The latter suggestion is in harmony with the obser-

vation that smoking increases the risk of lung cancer in womenwho receive estrogen replacement therapy (16, 17).

For pancreas, the risks are considerably higher for malesbut only significant for the category of 1-14 cigarettes per day,

for which males have a risk of 7.18 (95% CI, 2.31-22.3) andfemales have a risk of 1.52 (95% CI, 0.66-3.52).

Smoking lowers slightly the risk of endometrial cancer,

the reduction being significant in the 1-14 and 15-24 cigarettesper day smoking categories. The significance disappears from15-24 cigarettes per day category after adjustment for total




Table 10 Results of multivariate regression analysis

Measurement 10 years or less and more than 10 years before diagnosis.

Variable Site Sex�l0 years >10 years

No. RR P No. RR P

Anthropometric variables

Height (m) Breast Female 190 1.016 0.23 249 1.036 0.003

Kidney

All sites

Male

Male

33

650

1.1 17

1.01 1

<0.001

0.09

76

1 135

1.019

1.012

0.33

0.02

Weight (kg) Kidney

Urinary bladder

Female

Female

19

18

0.995

0.995

0.82

0.04

39

30

1.039

0.976

<0.001

0.18

BMI (kg/rn2) Stomach Male 76 0.906 0.005 95 0.960 0.20

Lung

Lung

Male

Female

99

89

0.942

0.926

0.05

0.007

174

1 10

0.917

0.920

<0.001

0.003

Body surface (m2) Urinary bladder

Brain

Female

Female

18

27

0.1 10

2.400

0.14

0.50

30

32

0.040

56.300

0.09

<0.001

Body fat (kg) Endometrium Female 33 1.016 0.08 65 1.017 0.02

Lean body mass (kg ) Stomach Female 39 0.95 1 0. 15 36 0.947 0.03

Pancreas Female 14 1.096 0.05 22 1.057 0.20

Serum measurements

Cholesterol (mmol/liter) Breast

All sites

Female

Female

190

642

0.930

0.920

0.23

0.02

249

848

0.900

0.950

0.07

0.09

Triclycerides (mmollliter) Colon and rectum Male 83 1.270 0.02 110 1.200 0.17

Endometrium

Thyroid

All sites

Female

Male

Female

33

16

642

1 .700

1.510

1.1 10

0.02

0.001

0.12

65

21

848

1 .360

0.800

1.130

0.46

0.60

0.06

Glucose. fasting (mmollliter) Prostate Male 144 1.080 0.32 360 1.130 0.06

Lymphoma Female 13 0.360 0.04 20 0.570 0.21

Glucose 90 mm (mmollliter) Colon and rectum

Leukemia

Female

Female

52

6

1.110

0.740

0.05

0.3 1

93

20

1.050

0.640

0.36

0.03

Creatinine (.smol/liter) Lung Male 99 0.980 0.01 174 0.989 0.09

Thyroid

Myeloma

All sites

Female

Female

Female

Female

89

27

10

642

0.968

0.995

0.922

0.999

0.19

0.77

0.005

0.83

1 10

19

13

848

0.979

1.003

0.942

1.0015

0.02

<0.001

0.03

<0.001

Uric acid (mmollliter) Pancreas

Urinary bladder

Female

Male

14

59

31

0.060

0.29

0.02

22

108

1.290

0.170

0.001

0.29

body fat. A protective effect of smoking on endometrial cancer

risk has also been found in case-control studies (18-20), givingsimilar results. It has been suggested that smoking causes

reduction in estrogen production (21); this, in turn, would be thecause of the reduction in risk for endometrial cancer. Theobservation, based on few cases only, that the negative risk of

endometrial cancer is confined to the lower categories of smok-ing suggests that heavy smoking may be a positive risk factor,

although moderate smoking reduces the risk.For urinary bladder, in males but not in females, all smok-

ing categories except 1-14 cigarettes a day are significantlypositive after adjustment for age.

Our study is prospective, and the information on smokingis obtained at one time; no information on lifetime smoking is

available. Our results indicate that there is a sex difference incarcinogenic effect of smoking because females have a higherrisk than do males in each smoking category for lung cancer.The reasons are unknown, but it seem more likely to be bio-

logical than due to classification bias of exposure. For cancer ofpancreas and urinary bladder, we find some evidence for higherrisk in males, but the information is not sufficient to give a clear

answer and more studies are needed. For the urinary bladder, itshould be kept in mind that elderly males are more likely thanfemales to have urine stagnant in the bladder, thus allowinglonger contact between possible carcinogens in the urine andthe urinary bladder epithelium.

Anthropometric Variables. Height is a significant positiverisk factor after adjustment for age for kidney in males and after

adjustment for age and cholesterol for breast in females, as wellas for all sites after adjustment for smoking in males. Short

stature was not a significant risk factor for any site, but it is apart of the body surface parameter, which is a negative risk

factor for stomach in males and for cervix in females. We havepreviously reported height as a significant risk factor for breast

cancer (4, 5), but it was first reported in 1974 (26). A thorough

review of the subject (27) found convincing evidence that

attained height is modestly associated with breast cancer risk.The review cites four prospective studies (28-31), which re-

ported RRs for pre- and postmenopausal women separately.One (28) found the risks to be the same, two (29, 30) found therisk to be higher for postmenopausal women, and one (31)

found the risk for premenopausal women to be higher. To lookfor the difference in breast cancer risk between pre- and post-menopausal women, subjects were classified by age at diagno-

sis into two groups, 343 women aged 55 years and older and 91below the age of 55. Because the age distribution of the cohort

depends on that of the Cardiovascular Study, there are rela-tively few in the younger group. The results are given in Table

9, but none of the anthropometric variables are significant forthe younger group, and the same variables are significant for the

older group as for the whole group of breast cancer patients.This study can not, therefore, throw light on the possibledifference between the above categories. After multiple regres-sion analysis, the risk of breast cancer associated with heightprevailed as 1.027 per cm, or 27% increases in risk for 10-cm

increments in height.




Weight is not a significantly positive risk factor for anysite in males, but it is a significant negative risk factor for

stomach and lung after adjustment for age only. These do notremain significant after multivariate regression analysis. For

females, weight is a significant positive risk factor for breast,endometrium, kidney, brain, and thyroid and a significant neg-

ative risk factor for esophagus, lung, and urinary bladder, afteradjustment for age only. After multivariate regression analysis,kidney remains a significant positive risk, and urinary bladderremains a significant negative risk. A recent population basedcase-control study from Denmark (32, 33) has found that

weight (reported as BMI) is a significant risk factor of kidney

cancer in women.BMI in males is a significant positive risk factor for

thyroid and a negative risk factor for stomach and lung, adjust-

ing for age only. After further adjustment for smoking andserum creatinine, it remains significant for lung. For females,

after adjustment for age only, the BMI is a significant positiverisk factor for endometrium, kidney, brain, and thyroid and asignificant negative risk factor for esophagus, lung, and urinary

bladder. After multivariate regression analysis, it remains asignificant negative risk factor only for lung. BMI, often re-

ferred to as relative weight or Quetlet’s index, which is weightin kilograms divided by height in meters, squared, has been

much used to describe the effect of overweight on cancer risk.Here, after stepwise multivariate regression analysis, it did not

remain a positive risk factor for any organ but remained as anegative risk factor for lung in both sexes and esophagus infemales. Other derived anthropometric parameters fit better.

Body surface in males is a significant positive risk factorfor kidney and a significant negative risk factor for stomach and

lung after adjustment for age only. It remains the only negativerisk factor for stomach after multivariate regression. For fe-

males, it is a significant positive risk factor for breast, endo-metrium, kidney, brain, and thyroid and a negative risk factor

for esophagus, lung, and cervix, after adjustment for age only.After multivariate regression, it remains a positive risk factorfor brain, and after adjustment for smoking and triglycerides, it

remains a significant negative risk factor for cervix.Body fat in males is a significant positive risk factor for

colon and rectum and a negative risk factor for esophagus andlung, after adjustment for age only. Only the negative risk for

esophagus remains significant after multivariate regression. Forfemales, it is a significant positive risk factor for endometrium,

brain, and thyroid and a negative risk factor for lung, afteradjustment for age only. After multivariate regression, itremains significant for endometrium after adjustment forsmoking.

Lean body mass in males is a significant positive riskfactor for kidney after adjustment for age only but not after

multivariate regression. For females, it is significantly positivefor pancreas, breast, endometrium, and brain and negative forstomach, lung, and cervix. After multivariate regression, it

remains a significant positive risk factor for pancreas, afteradjustment for smoking and uric acid, and a negative risk factorfor stomach.

The results indicate that the choice of parameter to de-scribe the body composition is of importance, and it is not the

best description of the data to use BMI only. It is, however, truethat if weight is significant, either positive or negative, BMI,

body surface, and body fat tend to show significance in thesame direction, as seen from Tables 3-8. Here, the correlation

coefficients between the variables have been computed: be-tween weight and body surface, 0.93 for each sex; betweenweight and BMI, 0.87 for males and 0.92 for females; between

weight and body fat, 0.56 for males and 0.64 for females; and

between weight and lean body mass, 0.55 for males and 0.62 for

females. Correlations between lean body mass and body surfaceare 0.7 1 for males and 0.73 for females. Correlations between

BMI and body surface are 0.67 for males and 0.74 for females.and between BMI and body fat, they are 0.60 for males and 0.66

for females.Weight or one of the other weight-related anthropometric

parameters appear as significant negative risk factors for esoph-agus in males (body fat) and females (BMI), stomach in males

(body surface) and in females (lean body mass), lung in males

(BMI) and in females (BMI), and cervix (body surface) andurinary bladder in females (weight). As significant positive risk

factors, they appear for colon and rectum for males (body fat),

for pancreas in females (lean body mass), endometrium (bodyfat), kidney in females (weight), and brain in females (body

surface). Thus, BMI appeared three times as a negative risk

factor, body surface appeared twice, and body fat, lean bodymass, and weight each appeared once. As positive risk factors,body fat appeared twice for males only, and body surface. lean

body mass, and weight each appeared once for females.It has been suggested that the risk from low body weight

can be explained as the effect of the malignancy after it has

started growing but before it can be diagnosed. If that were so,

the effect would be more marked in the first 10 years after the

measurement than when the interval is longer. To test this. therisk period was divided into two periods. The first period

comprises 10 years after examination, and the second com-

prises the time after 10 years. Cox’s regression was applied to

each period, as shown in Table 10. The only variable that shows

greater strength in the former periods than the later is serum

triglycerides. As a negative risk factor, BMI for lung in bothsexes is more significant in the later period.

Serum Measurements and Blood Pressure. Serum choles-terol does not remain a significant positive risk factor for any

site after multivariate stepwise regression analysis. It is a neg-ative risk factor for breast after adjustment for height and for all

sites in females after adjustment for smoking, triglycerides, and

creatinine. The early literature on the relationship between

serum cholesterol and subsequent risk of cancer has been re-

viewed previously (34). A thorough review of the literature up

to 1991 (35) concluded that evidence supported preclinicalcancer as a cause of lowering of serum cholesterol and provided

limited but biologically plausible evidence that men with nat-urally low serum cholesterol levels may be at increased risk ofcolon cancer. A cohort study of middle-aged British men re-

viewed the recent literature (36) and concluded that, in spite of

a significant increase in cancer risk, this could be due to

preclinical disease. Like low weight, this has been explained in

many publications as a result of the disease rather than preced-ing it, but here, it seems likely that both effects are at play

because cholesterol is a negative risk factor for breast cancer

more than 10 years before the diagnosis (0.90; P 0.07).

Cholesterol is a risk factor for all cancer for females and the risk

for less than 10 years interval is 0.92 (P = 0.02), based on 642

cases, but for more than 10 years interval, it is 0.95 (P = 0.09),based on 848 cases, as shown in Table 10.

Serum triglycerides are a significant positive risk factor forcolon and rectum for males and for thyroid after adjustment forthe use of drugs for hypertension. For females, they are a

significant positive risk factor for cervix after adjustment forsmoking and body surface and for all sites after adjustment for

smoking, cholesterol, and creatinine. In contrast to cholesterol.they are not a significant negative risk factor for any site in



872 Risk Factorsfor Malignant Diseases

multivariate analysis. As with smoking, they can be considered

a risk factor for both cardiovascular diseases and cancer. Of thevariables considered in Table 10, triglycerides show the mostpronounced preference for 10 or fewer years over the more than

10-year observation period between measurement and the di-agnosis of a malignancy, and this is more likely to be due to thepreclinical cancer rather than due to triglycerides acting as a

risk factor.

Fasting glucose is a significant positive risk factor for

prostate cancer and a negative risk factor for lymphoma infemales, and glucose, 90 mm after consumption, is a positiverisk factor for colon and rectum for females and a negative

risk factor for leukemia for females. Steenland et a!. (37)

reported diabetes as a significant risk factor for all sites formales and elevated risk for prostate cancer. For all sites, the

odds ratio in univariate regression analysis increased from1 .38 to 1 .77 when the analysis was restricted to cases diag-

nosed 6 or more years after the measurement (not shown inTables 1-10) Here, fasting glucose was a negative risk factor

for lymphomas in females and both sexes combined, andglucose, 90 mm after consumption, was a negative riskfactor for leukemia for females only. McKeown-Eyssen (38)

suggested that serum triglycerides and/or plasma glucose is

associated with the increased risk of cancer of colon orrectum. Here, triglycerides are significant for each sex inunivariate regression analysis, as is glucose at 90 mm after

consumption in multivariate regression for females, thussupporting the above-mentioned findings.

Diastolic blood pressure is a positive risk factor for thyroidcancer in females. Hypertension did not remain a risk factor forany site after stepwise multivariate regression analysis, but the

use of anti hypertensive drugs remained a positive risk factorfor thyroid cancer in males.

Conclusions. Because many significance tests have beenperformed, single observations have to be taken with cau-tion, but it seems possible to conclude that height is a risk

factor for kidney and breast and for all sites in males, andthat overweight may be overrated as a risk factor for malig-nant diseases in general but is a risk factor for kidney and

brain. In addition, body fat may be a risk factor for endo-

metrium and for colon and rectum in males, and lean bodymass may be a risk factor for pancreas in females. The use

of the measured and derived anthropometric parameters,height, weight, BMI, body surface, body fat, and lean bodymass, as well as other such parameters (39), may lead to newinformation on the pathogenesis of those malignant diseasesin which they seem to be risk factors. Weight and the otherrelated parameters are negative risk factors for lung, but for

urinary bladder in females, this is significant only in the first10 years after measurement (Table 10).

Appendix

Formulas for Calculating Anthropometric Measurements

L = 400*(H2*F*R)#{176}7#{176}

S - 0.2025 * W#{176}425* H#{176}7�

BF = W - L

B = W/H2

where L is lean body mass (kg). S is body surface (M2), BF is body fat (kg). Bis body mass index (kg/rn2). H is height (m), W is weight (kg), R is sum of left

and right radio ulnar measurements (m), and F is sum of left and right femur

condyl measurements (m).

Blood pressure (systolic and diastolic) is the mean value of measurements

at two visits to the clinic. Hypertension was defined as (a) systolic blood pressure

� 160 mm Hg and/or blood pressure �95 mm Hg on both measurements; or (b)blood pressure did not meet these criteria, but the subject was under antihyper-

tensive treatment.

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1997;6:863-873. Cancer Epidemiol Biomarkers Prev H Tulinius, N Sigfússon, H Sigvaldason, et al. population of 22,946 Icelanders.Risk factors for malignant diseases: a cohort study on a

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