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Cancer Screenee Cohort Study at National Cancer Center in Korea

Jeongseon Kim

Molecular Epidemiology Branch, National Cancer Center, Goyang-si, Korea

Correspondence should be addressed to: Jeongseon Kim, PhD

Molecular Epidemiology Branch, Division of Cancer Epidemiology and Prevention, Research

Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769,

Korea.

Tel: 82-31-920-2570

Fax: 82-31-920-2579

E-mail:jskim@ncc.re.kr

Running Title: The Cohort Study of National Cancer Center

Funding: This work was supported by the National Cancer Center Intramural Research Grant

(1210140).

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Cancer Screenee Cohort Study at National Cancer Center in Korea

ABSTRACT

Cancer screenee cohort study at National Cancer Center (NCC) was first established

in 2002 for the foundation of research studies to investigate all possible risk factors related to

cancers and to expand biological specimen banking to determine the effective methodology

for cancer detection, diagnosis, and prevention. As of May 23rd in 2014, total 40,709

participants are enrolled in this cohort study. The information on participants’ health included

questionnaire, clinical result, physical examination, cancer screening, and biological

specimen test including blood, urine, and exfoliated cervical cells. Thyroid cancer has been

the top occurring cancer type in a nested case-control study design when linked to national

cancer registry information as of December 31st, 2011. The studies related with chronic

diseases including cancer were published in scientific journals; case-controls, cross-sectional,

and cohort since 2009. Categorized by research topic, the studies related with diet and

nutrition were published the most, followed by gene, HBV and liver cancer screening,

methodology, physical activity, obesity, metabolic syndrome, smoking and alcohol

consumption, and blood type. The achievement of scientific evidence-based screenee cohort

study at NCC is highly anticipated to reduce the burden of cancer in Korean population for

cancer detection, diagnosis, and prevention for the next decades.

Keyword: National Cancer Center, cancer, cohort, Korea

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INTRODUCTION

A cohort study is one of observational research design types in which individuals

with the incidence of disease are compared with those who do not develop disease during

follow-up time. In Korea, the Korean Multi-center Cancer Cohort study (KMCC) with

biological materials bank was established in 4 geologically-defined urban and rural regions

with general population-based aged over 35 of male and female since 1993 [1]. The study

was designed to investigate the relationship between exposures to specific agents (e.g., life-

style) and the risk of cancers in Korean population. Another population-based prospective

cohort study, the Korean Genome and Epidemiology Study (KoGES), was initiated by the

Korea Centers for Disease Prevention and Control (KCDC) in 2001 [2]. The study was

designed to determine genetic and environmental risk factors of major chronic diseases such

as metabolic syndrome, diabetes, obesity, hypertension, cardiovascular disease, cancer, and

others. To collect large-scale epidemiological and clinical data as well as biospecimen, the

national infrastructure for biomedical research was established. Largely, there are 3 major

cohort studies established by KoGES; 1) community-based cohort (Ansan and Ansung,

n=10,038) and rural community-based cohort (n=28,000), 2) health-examinee cohort

(n=174,000), 3) special cohort (twin and family (n=3,300)), Korean emigrants (n=3,600),

marriage-based immigrants (n=7,500), and Asian Collaborative cohort (n=4,000). Through

the study, it has been expected that the burden of chronic diseases was significantly decreased

and improved quality of life in participants [2].

The countries such as the U.S., Japan, and other European countries have already

started large cohort studies in last few decades to investigate the association between risk

factors and the risk of cancers. For instance, the JPHC (the Japan Public Health Center-based

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Prospective study on Cancer and Cardiovascular Diseases), based on 11 public health centers

including the study population more than 140,000 participants, is designed to provide

scientific evidence-based information for cancer prevention and control of cardiovascular

diseases with a follow-up system since 1990 (cohort I) and 1993 (cohort II) [3]. In U.S., the

Nurse’s Health Study (NHS) started in 1976 primarily focused on women’s health,

particularly in cancer and other chronic health conditions [4]. In Europe, the European

Prospective Investigation into Cancer and Nutrition (EPIC) is a multi-center prospective

cohort study located in 23 centers in 10 European countries including more than 500,000

participants [5]. The study is designed to investigate the association between nutrition and

cancer using dietary questionnaire addressing with usual diet intake. In China, the Shanghai

Women’s Health Study (SWHS) was first established between 1996 and 2000, and recruited

about 75,000 adult Chinese women selected from urban communities to investigate the major

incidence of cancers based on anthropometric risk factors such as smoking, alcohol intake,

and others [6]. Parallel to the SWHS, the Shanghai Men’s Health Study (SMHS) including

total 61,500 adult Chinese men was first established between 2001 and 2006 to investigate

dietary and life-style factors associated with cancers and other chronic diseases in adult

Chinese men [7].

Comparing with cohort studies in other countries, the cancer screenee cohort study

was first established at the center for Cancer Prevention and Detection at National Cancer

Center (NCC) in 2002. Based on the health status of participants, the purpose of this study is

to investigate possible risk factors related to cancers and to expand biological specimen

banking to determine the effective methodology for cancer detection, diagnosis, and

prevention in Korean population. In last decades, cohort studies have been newly established

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and developed at governmental level. Particularly, NCC is one of the most representative

research agencies for cancer epidemiology, which is highly anticipated to reduce the burden

of cancer in Korean population for the next decades. This paper is to introduce the

establishment and achievements of screenee cohort study at NCC at both national and

international levels since 2002.

STUDY PARTICIPANTS

The total participants enrolled in this cohort study are 40,709, as of May 23rd, 2014,

aged between 30 and 70 years from August 2002. The demographic factors also included age,

gender, marital status, education level, household income, job, smoking, alcohol consumption,

and family history of cancer (Table 1). The participants who are agreed to enroll in this cohort

study were interviewed by trained personnel and conducted health examination including

questionnaire (e.g., past medical history), clinical tests (e.g., chest X-ray), physical

examination (e.g., blood pressure), cancer screening (e.g., Pap smear), blood test (e.g.,

cholesterol), urine test (e.g., routine urinalysis), and other biological specimen (e.g., buffy

coat) at the Center for Cancer Prevention and Detection at NCC (Table 2).The missing

information given by a participant to trained personnel is completed by telephone-contact

personnel. The current status of screenee cohort study includes; the total informed consent

(n=43,823), life-style questionnaire (n=42,021), plasma (n=38,138 [vial=158,098]), buffy

coat (n=38,110 [vial=73,911]), RBC (n=38,120 [vial=75,865]), serum (n=37,540

[vial=140,460]), whole blood (n=8,953 [vial=26,655]), extracted DNA (n=19,209), spot urine

(n=18,171), and uterine cervical exfoliated cells (n=6,442).

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ETHICAL CONSIDERATIONS

In August 2002, this study was approved by the institutional review board (IRB) of

NCC. All participants agreed with informed consent have the right to withdraw from the

study at any time without penalty. The participants were fully informed by trained personnel

in terms of the purpose of this study that supports for cancer detection, diagnosis, and

prevention at national level.

MEASUREMENTS: INCIDENCE OF CANCER CASES

Based on resident registration number matching with participants, the incidence of

cancer cases in the cancer screenee cohort study was confirmed by linking to the Korea

National Cancer Incidence Database (KNCI DB) from the Korea Central Cancer Registry

(KCCR) [8]. Using the incidence of all cancer cases (n=1,498, male=824, female=674) in

screenee cohort as of December 31st, 2011, the incidence of thyroid cancer was the highest

(n=507) in male (n=184) and female (n=323) compared with other cancer types, followed by

stomach (n=189, 128M, 61F), colorectum (n=155, 103M, 52F), lung (n=123, 83M, 40F),

breast (n=107, 1M, 106F), prostate (N=99, 99M), liver (n=67, 58M, 9F), kidney (n=28, 25M,

3F), bladder (n=27, 25M, 2F), gallbladder (n=17, 12M, 5F), and pancreas cancer (n=15, 14M,

1F) in a nested case-control study design (Table 3) [9].

KEY FINDINGS: PUBLICATIONS

The studies were published in scientific journals since 2009; diet and nutrition (n=14),

gene (n=5), HBV and liver cancer screening (n=3), methodology (n=3), physical activity

(n=2), obesity (n=2), metabolic syndrome (n=1), smoking and alcohol consumption (n=1),

and blood type (n=1). Of these published studies, case-control studies were published the

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most (n=17), followed by cross-sectional (n=13), and cohort (n=2) (Table 4). At NCC, cross-

sectional studies primarily using a self-questionnaire investigated the association between the

risk factors (e.g., diet, physical activity, smoking, and alcohol consumption) and chronic

diseases (e.g., obesity, osteoporosis, and metabolic syndrome and colorectal adenomas).

Particularly, the incidence of liver cancer was associated with subject’s life-style, such as

socioeconomic and health examination status. In case-control studies, an individual with a

certain disease was compared with healthy individual using biological specimen, although we

should be very careful when interpreting the study results due to selection and recall biases in

particular in such a hospital-based study designs, which are different in community-based

counterparts. In addition, a nested case-control study within the screenee cohort for thyroid

cancer is currently on progress, and is expected to research on stomach, lung, and prostate

cancer for the next three to four years. However, cancers with low incidence rates will require

a more active follow-up for a long-term period. Using the database through the screenee

cohort study at NCC, it is anticipated to determine the risk factors of cancers. It is also

expected to create a scientific model to determine the cause of cancer from the interaction

between genetic and environmental factors, and provide evidence-based personalized

preventive medicine. Moreover, it will be applicable for designing, evaluating, and providing

information for the national cancer control policy, and exchanging in scientific knowledge

and manpower in coordinated research projects at national and international levels.

CONFLICT OF INTEREST

The author has no conflicts of interest to declare for this study.

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ACKNOWLEDGEMENT

This manuscript was written with the help of Jeonghee Lee and Wook Jin Choi, who have

been working as researchers in Molecular Epidemiology Branch at National Cancer Center

with a grant support of National Cancer Center, Korea (1210140).

REFERENCES

1. Yoo KY, Shin HR, Chang SH, Lee KS, Park SK, Kang D, et al. Korean Multi-center Cancer Cohort Study including a biological materials bank (KMCC-I). Asian Pac J Cancer Prev 2002;3(1):85-92. 2. The Korean Society of Epidemiology. Korean Genonme and Epidemiology Study: KoGES (abstract): 2013 fall academic conference proceedings. 2013, p. 93-104 (Korean). 3. Tsugane S, Sobue T. Baseline survey of JPHC study--design and participation rate. Japan Public Health Center-based Prospective Study on cancer and cardiovascular diseases. J Epidemiol 2001;11(6 Suppl):S24-29. 4. International Agency for Research on Cancer (IARC). Cancer epidemiology: principles and methods. Lyon: IARC press; 1999, p. 165-187. 5. Riboli E, Hunt K, Slimani N, Ferrari P, Norat T, Fahey M, et al. European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr 2002;5(6b):1113-1124. 6. Zheng W, Chow WH, Yang G, Jin F, Rothman N, Blair A, et al. The Shanghai Women's Health Study: rationale, study design, and baseline characteristics. Am J Epidemiol 2005;162(11):1123-1131. 7. National Cancer Institute. Cohort Consortium. Shanghai Men's Health Study: cohort study of cancer - inhibitory factors in men; 2013 [cited 2014 May 26]. Available from: http://epi.grants.cancer.gov/Consortia/members/smhs.html 8. The Korea Central Cancer Registry. Annual report of cancer statistics in Korea in 2010; 2012 [cited 2014 May 26]. Available from http://ncc.re.kr/manage/manage03_033_view.jsp?bbsnum=250&hSelSearch=&hTxtKeyword=&current_page=1&cd=null (Korean). 9. The Korea Central Cancer Registry. Annual report of cancer statistics in Korea in 2011; 2013 [cited 2014 May 26]. Available from http://ncc.re.kr/manage/manage03_033_view.jsp?bbsnum=295&hSelSearch=&hTxtKeyword=&current_page=1&cd=null (Korean).

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Table 1. Distribution of the cohort by selected demographic factors

Variables Male (N=20,519)

Female (N=20,190)

Total (N=40,709)

Age groups 30-39 2,771(13.5) 2,551(12.6) 5,322(13.1) 40-49 7,528(36.7) 7,700(38.1) 15,228(37.4) 50-59 6,550(31.9) 6,792(33.6) 13,342(32.8) 60-70 3,670(17.9) 3,147(15.6) 6,817(16.8) Marital status Never married 621( 3.0) 657( 3.3) 1,278( 3.1) Presently married 17,925(87.4) 15,898(78.7) 33,823(83.1) Widowed 162( 0.8) 1,011( 5.0) 1,173( 2.9) Divorced/separated 367( 1.8) 783( 3.9) 1,150( 2.8) Unknown 1,444( 7.0) 1,841( 9.1) 3,285( 8.1) Education level

Under middle school 2,068(10.1) 3,437(17.0) 5,505(13.5) High school 5,541(27.0) 7,598(37.6) 13,139(32.3) College or more 11,182(54.5) 6,870(34.0) 18,052(44.3) Unknown 1,728( 8.4) 2,285(11.3) 4,013( 9.9)

Household income (1,000won/month)

<200 2,244(10.9) 3,143(15.6) 5,387(13.2) 200-400 5,739(28.0) 5,221(25.9) 10,960(26.9) >400 9,722(47.4) 7,363(36.5) 17,085(42.0) Unknown 2,814(13.7) 4,463(22.1) 7,277(17.9)

Job Profession, administration 6,638(32.4) 1,851( 9.2) 8,489(20.9) Office worker 3,450(16.8) 1,409( 7.0) 4,859(11.9) Sales, services 3,771(18.4) 2,567(12.7) 6,338(15.6) Agriculture, labor, other 3,227(15.7) 980( 4.9) 4,207(10.3) Housewife 15( 0.1) 10,771(53.3) 10,786(26.5) Unemployed, retire 1,654( 8.1) 532( 2.6) 2,186( 5.4) Unknown 1,764( 8.6) 2,080(10.3) 3,844( 9.4) Smoking status Never smoker 3,797(18.5) 16,207(80.3) 20,004(49.1) Ex-smoker 7,829(38.2) 660( 3.3) 8,489(20.9) Current smoker 7,894(38.5) 886( 4.4) 8,780(21.6) Unknown 999( 4.9) 2,437(12.1) 3,436( 8.4) Alcohol consumption Never drinker 2438(11.9) 9800(48.5) 12238(30.1) Ex-drinker 1322( 6.4) 830( 4.1) 2152( 5.3) Current drinker 15767(76.8) 7763(38.4) 23530(57.8) Unknown 992( 4.8) 1797( 8.9) 2789( 6.9) Family history of cancer

No 6,492(31.6) 6,743(33.4) 13,235(32.5) Yes 13,119(63.9) 12,079(59.8) 25,198(61.9) Missing 908( 4.4) 1,368( 6.8) 2,276( 5.6)

Data are presented as population (%)

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Table 2. Health examination tests in screenee cohort participants

Questionnaire/Tests Measurements

Questionnaire

Demographics, past medical history, family history of disease, occupation, medication, smoking including environmental tobacco smoking, alcohol habits, food frequency questionnaire (food items/groups) or 3-day dietary records, female reproductive history

Clinical Tests

Electrocardiogram, pulmonary function test, chest X-ray, body composition analysis (Impedance), bone density (DEXA)

Physical

Measurement Blood pressure, pulse, height, weight, waist circumference, visual acuity test

Cancer Screening

Esophagogastroduodenoscopy, mammography, cytology of cervix uteri (pap smear), stool occult blood/colono-sigmoido-scopy/liver USG + aFP

Blood Test

Fasting plasma glucose, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol (direct measure), triglyceride, total protein, albumin, gamma-glutamyl transferase, aspartate aminotransferase, alanine amino transferase, creatinine, calcium, uric acid, complete blood cell count with differential count

Urine Tests Routine urinalysis

Biological

Specimens Plasma, buffy coat, red blood cell, serum, whole blood, extracted DNA, random spot urine, uterine cervical exfoliated cells (women)

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Table 3. The number of cancer incidence cases*

Subsites Men Women Total

Thyroid 184 323 507

Stomach 128 61 189

Colorectum 103 52 155

Lung 83 40 123

Breast 1 106 107

Prostate 99 - 99

Liver 58 9 67

Kidney 25 3 28

Bladder 25 2 27

Gallbladder 12 5 17

Pancreas 14 1 15

All Cancers 824 674 1,498

*Data presented in cancer screenee cohort study was linked to the Korean National Cancer incidence database from the Korea Central Cancer Registry as of December 31st, 2011 [9].

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Table 4. The lists of papers published through screenee cohort study

Diet Study Type1. Kim J, Lim SY, Shin A, Sung MK, Ro J, Kang HS, et al. Fatty fish and fish

omega-3 fatty acid intakes decrease the breast cancer risk: a case-control study. BMC Cancer. 2009;9:216.

CC

2. Shin A, Lim SY, Sung J, Shin HR, Kim J. Dietary intake, eating habits, and metabolic syndrome in Korean men. J Am Diet Assoc. 2009;109(4):633-640.

CS

3. Yu H, Hwang JY, Ro J, Kim J, Chang N. Vegetables, but not pickled vegetables, are negatively associated with the risk of breast cancer. Nutr Cancer. 2010;62(4):443-453.

CC

4. Shin A, Kim J, Lim SY, Kim G, Sung MK, Lee ES, et al. Dietary mushroom intake and the risk of breast cancer based on hormone receptor status. Nutr Cancer. 2010;62(4):476-483.

CC

5. Cho YA, Kim J, Park KS, Lim SY, Shin A, Sung MK, et al. Effect of dietary soy intake on breast cancer risk according to menopause and hormone receptor status. Eur J Clin Nutr. 2010;64(9):924-932.

CC

6. Cho YA, Kim J, Shin A, Park KS, Ro J. Dietary patterns and breast cancer risk in Korean women. Nutr Cancer. 2010;62(8):1161-1169.

CC

7. Kim J, Lee JS, Shin A, Kang MH, Shin DS, Chung HR, et al. Sociodemographic and lifestyle factors are associated with the use of dietary supplements in a Korean population. J Epidemiol. 2010;20(3):197-203.

CS

8. Shin A, Lim S, Sung J, Myung S, Kim J. Dietary habit and bone mineral density in Korean postmenopausal women. Osteoporos Int. 2010;21(6):947-955.

CS

9. Cho ER, Shin A, Lim SY, Kim J. Dietary patterns and their associations with health behaviours in Korea. Public Health Nutr. 2011;14(2):356-364.

CS

10. Cho YA, Shin A, Kim J. Dietary patterns are associated with body mass index in a Korean population. J Am Diet Assoc. 2011;111(8):1182-1186.

CS

11. Cho YA, Kim J, Cho ER, Shin A. Dietary patterns and the prevalence of metabolic syndrome in Korean women. Nutr Metab Cardiovasc Dis. 2011;21(11):893-900.

CS

12. Youn S, Woo HD, Cho YA, Shin A, Chang N, Kim J. Association between dietary carbohydrate, glycemic index, glycemic load, and the prevalence of obesity in Korean men and women. Nutr Res. 2012;32(3):153-159.

CS

13. Kim KZ, Shin A, Kim J, Park JW, Park SC, Choi HS, et al. Association between CASR polymorphisms, calcium intake, and colorectal cancer risk. PLoS One. 2013;8(3):e59628.

CC

14. Woo HD, Park KS, Shin A, Ro J, Kim J. Glycemic index and glycemic load dietary patterns and the associated risk of breast cancer: a case-control study. Asian Pac J Cancer Prev. 2013;14(9):5193-5198.

CC

Gene 1. Yoon KA, Park S, Hwangbo B, Shin HD, Cheong HS, Shin HR, et al. Genetic

polymorphisms in the Rb-binding zinc finger gene RIZ and the risk of lung cancer. Carcinogenesis. 2007;28(9):1971-1977.

CC

2. Miki D, Kubo M, Takahashi A, Yoon KA, Kim J, Lee GK, et al. Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations. Nat Genet. 2010;42(10):893-896.

CC

3. Yoon KA, Park JH, Han J, Park S, Lee GK, Han JY, et al. A genome-wide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population. Hum Mol Genet. 2010;19(24):4948-4954.

CC

4. Joung JY, Lee YS, Park S, Yoon H, Lee SJ, Park WS, et al. Haplotype analysis of CC

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prostate stem cell antigen and association with prostate cancer risk. J Urol. 2011;185(6):2112-2118.

5. Joung JY, Park S, Yoon H, Lee SJ, Park WS, Seo HK, et al. Association of common variations of 8q24 with the risk of prostate cancer in Koreans and a review of the Asian population. BJU Int. 2012;110(6 Pt B):E318-325.

CC

HBV and Liver Cancer Screening 1. Shin A, Cho ER, Kim J, Sung J, Park KW, Lim MK, et al. Factors associated

with awareness of infection status among chronic hepatitis B and C carriers in Korea. Cancer Epidemiol Biomarkers Prev. 2009;18(6):1894-1898.

CS

2. Yun EH, Lim MK, Oh JK, Park JH, Shin A, Sung J, et al. Combined effect of socioeconomic status, viral hepatitis, and lifestyles on hepatocelluar carcinoma risk in Korea. Br J Cancer. 2010;103(5):741-746.

CS

3. Cho ER, Shin A, Choi KS, Lee HY, Kim J. Factors associated with use of ultrasonography screening for hepatocellular carcinoma among hepatitis B or C carriers. Cancer Epidemiol. 2010;34(6):713-716.

CS

Methodology 1. Lee DH, Shin A, Kim J, Yoo KY, Sung J. Validity of self-reported height and

weight in a Korean population. J Epidemiol. 2011;21(1):30-36. CS

2. Park B, Ma SH, Shin A, Chang MC, Choi JY, Kim S, et al. Korean risk assessment model for breast cancer risk prediction. PLoS One. 2013;8(10):e76736.

CC

3. Lee JH, Kim KH, Park JW, Chang HJ, Kim BC, Kim SY, et al. Low-mass-ion discriminant equation: a new concept for colorectal cancer screening. Int J Cancer. 2014;134(8):1844-1853.

CC

Physical Activity 1. Cho ER, Shin A, Kim J, Jee SH, Sung J. Leisure-time physical activity is

associated with a reduced risk for metabolic syndrome. Ann Epidemiol. 2009;19(11):784-792.

CS

2. Kim KZ, Shin A, Lee J, Myung SK, Kim J. The beneficial effect of leisure-time physical activity on bone mineral density in pre- and postmenopausal women. Calcif Tissue Int. 2012;91(3):178-185.

CS

Obesity 1. Nam SY, Choi IJ, Nam BH, Park KW, Kim CG. Obesity and weight gain as risk

factors for erosive oesophagitis in men. Aliment Pharmacol Ther. 2009;29(9):1042-1052.

CO

2. Boffetta P, Hazelton WD, Chen Y, Sinha R, Inoue M, Gao YT, et al. Body mass, tobacco smoking, alcohol drinking and risk of cancer of the small intestine--a pooled analysis of over 500,000 subjects in the Asia Cohort Consortium. Ann Oncol. 2012;23(7):1894-1898.

CO

Metabolic Syndrome 1. Kim BC, Shin A, Hong CW, Sohn DK, Han KS, Ryu KH, et al. Association of

colorectal adenoma with components of metabolic syndrome. Cancer Causes Control. 2012;23(5):727-735.

CC

Smoking & Alcohol consumption 1. Shin A, Hong CW, Sohn DK, Chang Kim B, Han KS, Chang HJ, et al.

Associations of cigarette smoking and alcohol consumption with advanced or multiple colorectal adenoma risks: a colonoscopy-based case-control study in Korea. Am J Epidemiol. 2011;174(5):552-562.

CC

Blood Type 1. Woo SM, Joo J, Lee WJ, Park SJ, Han SS, Kim TH, et al. Risk of pancreatic CC

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cancer in relation to ABO blood group and hepatitis C virus infection in Korea: a case-control study. J Korean Med Sci. 2013;28(2):247-251.

CC, case-control. CS, cross-sectional. CO, cohort