GECCO: Detecting Common and Rare Genetic Loci and GxE Interactions in Colorectal Cancer

COLON, Colorectal Cancer: Longitudinal Observational study on Nutritional and lifestyle factors that influence colorectal tumor recurrence, survival and quality of life: The COLON study is a multi-center prospective cohort study to assess the role of diet and other lifestyle factors in cancer recurrence and survival among incident colorectal cancer patients in the Netherlands. DACHS, Darmkrebs: Chancen der Verhütung durch Screening:This German study was initiated as a large population-based case-control study in 2003 in the Rhine-Neckar-Odenwald region (southwest region of Germany) to assess the potential of endoscopic screening for reduction of colorectal cancer risk and to investigate etiologic determinants of disease, particularly lifestyle/environmental factors and genetic factors. During an in-person interview, data were collected on demographics, medical history, family history of CRC, and various life-style factors, as were blood and mouthwash samples. EPIC, European Prospective Investigation into Cancer: EPIC is an on-going multicenter prospective cohort study designed to investigate the associations between diet, lifestyle, genetic and environmental factors and various types of cancer. HPFS, Health Professionals Follow-up Study: HPFS is a parallel prospective study to the NHS. The HPFS cohort comprised 51,529 men aged 40-75 who, in 1986, responded to a mailed questionnaire. Participants provided information on health related exposures, including current and past smoking history, age, weight, height, diet, physical activity, aspirin use, and family history of colorectal cancer. Colorectal cancer and other outcomes were reported by participants or next-of-kin and were followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical record review. Information was abstracted on histology and primary location. Follow-up evaluation has been excellent, with 94% of the men responding to date. NHS, Nurses' Health Study: The NHS cohort began in 1976 when 121,700 married female registered nurses age 30-55 years returned the initial questionnaire that ascertained a variety of important health-related exposures [PMID:248266]. Since 1976, follow-up questionnaires have been mailed every 2 years. Colorectal cancer and other outcomes were reported by participants or next-of-kin and followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical-record review. Information was abstracted on histology and primary location. The rate of follow-up evaluation has been high: as a proportion of the total possible follow-up time, follow-up evaluation has been more than 92%. NQplus, Nutrition Questionnaires plus: NQplus is a longitudinal observational study on diet and health in the general Dutch population. ]]> COLON, Colorectal Cancer: Longitudinal Observational study on Nutritional and lifestyle factors that influence colorectal tumor recurrence, survival and quality of life: Patients with colorectal cancer from 11 hospitals were invited upon diagnosis. Patients with a history of colorectal cancer or (partial) bowel resection, chronic inflammatory bowel disease, hereditary colorectal cancer syndromes, or dementia were excluded from the study. At diagnosis and at several time points during follow-up, patients donated a blood sample and filled out questionnaires about diet and other lifestyle factors. Blood samples are stored in a biobank to facilitate future analyses. Information on vital status is retrieved by linkage with national registries. Information on clinical characteristics is gathered from linkage with the Netherlands Cancer Registry and with hospital databases. A total of 743 colorectal cancer samples were selected for genotyping. Matching controls were selected from the NQplus study described below. DACHS, Darmkrebs: Chancen der Verhütung durch Screening: Cases with a first diagnosis of invasive colorectal cancer (International Classification of Diseases 10 codes C18-C20) who were at least 30 years of age (no upper age limit), German speaking, a resident in the study region, and mentally and physically able to participate in a one-hour interview, were recruited by their treating physicians either in the hospital a few days after surgery, or by mail after discharge from the hospital. Cases were confirmed based on histologic reports and hospital discharge letters following diagnosis of colorectal cancer. All hospitals treating colorectal cancer patients in the study region participated. Community-based controls were randomly selected from population registries, employing frequency matching with respect to age (5-year groups), sex, and county of residence. Controls with a history of colorectal cancer were excluded. Controls were contacted by mail and follow-up calls. In total 1268 cases and 634 matched controls were selected for genotyping. EPIC, European Prospective Investigation into Cancer: In summary, 521,448 participants (~70% women) mostly aged 35 years or above were recruited between 1992 and 2000. Participants were recruited from 23 study centers in ten European countries. The current study included participants from France, Germany, Greece, Italy, the Netherlands, Spain, Sweden, and United Kingdom (UK). Blood samples were collected at baseline according to standardized procedures, and stored at the International Agency for Research on Cancer (IARC; -196ºC, liquid nitrogen) for all countries except Sweden (-80ºC freezers). All study participants provided written informed consent. Ethical approval for the EPIC study was obtained from the review boards of IARC and local participating centers. Incident cancer cases were identified using population cancer registries in Italy, the Netherlands, Spain, and the United Kingdom. In France, Germany and Greece cancer cases were identified during follow-up by a combination of methods including: health insurance records, cancer and pathology registries, and by active follow-up directly through study participants or through next-of-kin. Controls were selected from the full cohort of individuals who were alive and free of cancer (except non-melanoma skin cancer) at the time of diagnoses of the cases, using incidence density sampling and matched by: age (±6 months at recruitment), sex, study center, follow-up time since blood collection, time of day at blood collection (±4 hours), fasting status, menopausal status, and phase of menstrual cycle at blood collection. The current study selected 2,400 incident colorectal cancer cases, and 2,400 matched controls. HPFS, Health Professionals Follow-up Study: In 1993-1995, 18,825 men in the HPFS mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 13,956 men in the HPFS who had not provided a blood sample previously, mailed in a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1986, but before the subject provided either a blood or buccal sample. After excluding participants with histories of cancer (except non-melanoma skin cancer), ulcerative colitis, or familial polyposis, 2 case-control sets were constructed from which DNA was isolated from either buffy coat or buccal cells for genotyping, as follows: (1) a case-control set with cases of colorectal cancer matched to randomly selected controls who provided a blood sample and were free of colorectal cancer at the same time the colorectal cancer was diagnosed in the cases; and (2) a case-control set with cases of colorectal cancer matched to randomly selected controls who provided a buccal sample and were free of colorectal cancer at the same time the colorectal cancer was diagnosed in the case. For both case-control sets, matching criteria included year of birth (within 1 year) and month/year of blood or buccal cell sampling (within 6 months). Cases were pair-matched 1:1, 1:2, or 1:3 with a control participant(s). For this study, colorectal cancer cases were ascertained through January 1, 2010 and excluded cases included in the previous discovery GWAS of colorectal cancer [PMID:23266556]. If no control could be matched for a case using the initial stringent criteria, age criteria were relaxed to <5 years to find an eligible control. A total of 237 CRC cases and 236 controls were selected for genotyping. NHS, Nurses' Health Study:In 1989-1990, 32,826 women in NHS I mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 29,684 women in NHS I who did not previously provide a blood sample mailed a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1976 but before the subject provided either a blood or buccal sample. After excluding participants with histories of cancer (except non-melanoma skin cancer), ulcerative colitis, or familial polyposis, 2 case-control sets were constructed from which DNA was isolated from either buffy coat or buccal cells for genotyping: (1) a case-control set with cases of colorectal cancer matched to randomly selected controls who provided a blood sample and were free of colorectal cancer at the same time the colorectal cancer was diagnosed in the case; and (2) a case-control set with cases of colorectal cancer matched to randomly selected controls who provided a buccal sample and were free of colorectal cancer at the same time the colorectal cancer was diagnosed in the cases. For this study, colorectal cancer cases were ascertained through June 1, 2012 and excluded cases included in the previous discovery GWAS of colorectal cancer [PMID:23266556]. For both case-control sets, matching criteria included year of birth (within 1 year) and month/year of blood or buccal cell sampling (within 1 year). If no control could be matched for a case using the initial stringent criteria, age criteria were relaxed to <5 years to find an eligible control. Cases were pair matched 1:1, 1:2, or 1:3 with a control participant(s). A total of 370 CRC cases and 370 controls were selected for genotyping. NQplus, Nutrition Questionnaires plus: A total of 2,048 participants were recruited by inviting randomly selected inhabitants of the neighboring cities Wageningen, Ede, Renkum and Arnhem. In Veenendaal, another neighboring city, one individual of each household was invited to participate in the NQplus study. Baseline measurements consisted of a fasting venipuncture, dietary assessment, a physical examination, 24-h urine collection and general and lifestyle questionnaires. For this study, 179 persons without a blood sample, and those with a history of colorectal cancer, chronic inflammatory bowel disease or dementia were excluded. From the remaining 1,869 NQplus participants, controls were selected, whom were matched to the colorectal cancer cases of the COLON study by age and gender. A total of 737 control samples were selected for genotyping. ]]>本数据集涵盖六项结直肠癌相关的临床与流行病学研究，具体如下： ### 研究概述 1. **COLON（结直肠癌）研究**：一项针对影响结直肠肿瘤复发、生存与生活质量的营养与生活方式因素的纵向观察性研究。COLON研究为多中心前瞻性队列研究，旨在评估饮食及其他生活方式因素在荷兰新发结直肠癌患者的癌症复发与生存情况中的作用。 2. **DACHS（结直肠癌：筛查预防的机遇）研究**：这项德国研究于2003年在莱茵-内卡-奥登瓦尔德地区（德国西南部）启动，为大型人群为基础的病例对照研究，旨在评估内镜筛查降低结直肠癌风险的潜力，并探究疾病的病因决定因素，尤其是生活方式/环境因素与遗传因素。研究通过面对面访谈收集人口统计学资料、病史、结直肠癌（Colorectal Cancer, CRC）家族史及各类生活方式因素相关数据，同时采集血液与漱口水样本。 3. **EPIC（欧洲癌症前瞻性调查）研究**：EPIC是一项正在进行中的多中心前瞻性队列研究，旨在探究饮食、生活方式、遗传与环境因素和各类癌症之间的关联。 4. **HPFS（卫生专业人员随访研究）**：HPFS是与NHS（护士健康研究）平行开展的前瞻性研究。HPFS队列纳入1986年回复邮寄问卷的51529名年龄40~75岁的男性。参与者提供健康暴露相关信息，包括当前及既往吸烟史、年龄、体重、身高、饮食、体力活动、阿司匹林使用情况及结直肠癌家族史。结直肠癌及其他结局由参与者或其近亲属报告，并由医师通过审阅医疗与病理记录随访确认。总体而言，超过97%的自我报告结直肠癌经医疗记录审阅得到确认。研究提取了肿瘤组织学类型与原发部位的相关信息。随访评估情况良好，截至目前已有94%的男性完成随访回复。 5. **NHS（护士健康研究）**：NHS队列始于1976年，当时121700名年龄30~55岁的已婚注册护士回复初始问卷，明确了多种重要健康相关暴露因素[PMID:248266]。自1976年起，每2年邮寄一次随访问卷。结直肠癌及其他结局由参与者或其近亲属报告，并由医师通过审阅医疗与病理记录随访确认。总体而言，超过97%的自我报告结直肠癌经医疗记录审阅得到确认。研究提取了肿瘤组织学类型与原发部位的相关信息。随访评估率较高：以总潜在随访时间占比计算，随访评估完成率超过92%。 6. **NQplus（营养问卷附加研究）**：NQplus是一项针对荷兰普通人群饮食与健康状况的纵向观察性研究。 ### 各研究详细内容 #### COLON研究详细信息 研究在患者确诊后邀请11家医院的结直肠癌患者参与。排除有结直肠癌病史或（部分）肠切除术史、慢性炎症性肠病、遗传性结直肠癌综合征或痴呆的患者。在确诊时及随访期间的多个时间点，患者捐献血液样本并填写关于饮食及其他生活方式因素的问卷。血液样本存储于生物样本库（biobank）以支持后续分析。通过与国家登记系统联动获取患者生存状态信息，通过与荷兰癌症登记处及医院数据库联动收集临床特征信息。最终共选取743份结直肠癌样本用于基因组分型（genotyping），匹配对照样本从下文所述的NQplus研究中选取。 #### DACHS研究详细信息 研究对象为首次诊断为浸润性结直肠癌（国际疾病分类第10版编码C18~C20）、年龄≥30岁（无年龄上限）、德语流利、居住于研究区域且身心状况可参与1小时访谈的患者，由接诊医师在术后数天于医院内招募，或在患者出院后通过邮寄方式招募。病例经结直肠癌诊断后的组织学报告及出院证明确认。研究区域内所有收治结直肠癌患者的医院均参与本研究。以年龄（5岁组）、性别及居住县为频率匹配因素，从人口登记系统中随机选取社区对照。排除有结直肠癌病史的对照。通过邮寄及随访电话联系对照。最终共选取1268名病例及634名匹配对照用于基因组分型。 #### EPIC研究详细信息 总体而言，该研究于1992年至2000年间招募521448名参与者（约70%为女性），其中大多数年龄≥35岁。参与者来自10个欧洲国家的23个研究中心，本研究纳入其中来自法国、德国、希腊、意大利、荷兰、西班牙、瑞典及英国（UK）的参与者。基线时按照标准化流程采集血液样本，除瑞典采用-80℃冰箱存储外，其余国家的样本均存储于国际癌症研究机构（International Agency for Research on Cancer, IARC）的液氮环境（-196℃）中。所有研究参与者均签署书面知情同意书。EPIC研究的伦理批准由IARC及各本地参与中心的伦理审查委员会出具。在意大利、荷兰、西班牙及英国，通过人群癌症登记系统识别新发癌症病例；在法国、德国及希腊，则通过健康保险记录、癌症与病理登记系统，以及直接对研究参与者或其近亲属进行主动随访等组合方式，在随访期间识别癌症病例。对照选自病例诊断时仍存活且无癌症（非黑色素瘤皮肤癌除外）的完整队列人群，采用发病密度抽样方法，并按照以下因素进行匹配：招募时年龄（±6个月）、性别、研究中心、采血后的随访时间、采血时段（±4小时）、空腹状态、绝经状态及采血时的月经周期阶段。本研究共选取2400名新发结直肠癌病例及2400名匹配对照。 #### HPFS研究详细信息 1993年至1995年间，HPFS队列中的18825名男性通过隔夜快递邮寄血液样本，样本被分装为棕黄层并存储于液氮中。2001年至2004年间，此前未提供血液样本的13956名HPFS参与者邮寄了含漱-吐取口腔细胞样本。新发病例定义为参与者提供血液或口腔细胞样本后发生的病例；现患病例定义为1986年研究入组后、但在参与者提供血液或口腔细胞样本前发生的病例。在排除有癌症史（非黑色素瘤皮肤癌除外）、溃疡性结肠炎或家族性腺瘤性息肉病的参与者后，构建2个病例对照数据集，从棕黄层或口腔细胞中提取DNA用于基因组分型，具体如下：(1) 结直肠癌病例对照数据集：将结直肠癌病例与随机选取的、提供了血液样本且在病例确诊结直肠癌时未患结直肠癌的对照进行匹配；(2) 另一结直肠癌病例对照数据集：将结直肠癌病例与随机选取的、提供了口腔细胞样本且在病例确诊结直肠癌时未患结直肠癌的对照进行匹配。两个数据集的匹配标准均包括出生年份（±1年）及血液/口腔细胞采样的年月（±6个月）。病例按照1:1、1:2或1:3的比例与对照参与者进行配对匹配。本研究的结直肠癌病例随访至2010年1月1日，且排除了此前结直肠癌发现性全基因组关联研究（Genome-Wide Association Study, GWAS）中纳入的病例[PMID:23266556]。若按照初始严格标准无法为病例找到匹配对照，则将年龄匹配范围放宽至±5年以寻找合格对照。最终共选取237名结直肠癌（CRC）病例及236名对照用于基因组分型。 #### NHS研究详细信息 1989年至1990年间，NHS I队列中的32826名女性通过隔夜快递邮寄血液样本，样本被分装为棕黄层并存储于液氮中。2001年至2004年间，此前未提供血液样本的29684名NHS I参与者邮寄了含漱-吐取口腔细胞样本。新发病例定义为参与者提供血液或口腔细胞样本后发生的病例；现患病例定义为1976年研究入组后、但在参与者提供血液或口腔细胞样本前发生的病例。在排除有癌症史（非黑色素瘤皮肤癌除外）、溃疡性结肠炎或家族性腺瘤性息肉病的参与者后，构建2个病例对照数据集，从棕黄层或口腔细胞中提取DNA用于基因组分型：(1) 结直肠癌病例对照数据集：将结直肠癌病例与随机选取的、提供了血液样本且在病例确诊结直肠癌时未患结直肠癌的对照进行匹配；(2) 另一结直肠癌病例对照数据集：将结直肠癌病例与随机选取的、提供了口腔细胞样本且在病例确诊结直肠癌时未患结直肠癌的对照进行匹配。本研究的结直肠癌病例随访至2012年6月1日，且排除了此前结直肠癌发现性GWAS中纳入的病例[PMID:23266556]。两个数据集的匹配标准均包括出生年份（±1年）及血液/口腔细胞采样的年月（±1年）。若按照初始严格标准无法为病例找到匹配对照，则将年龄匹配范围放宽至±5年以寻找合格对照。病例按照1:1、1:2或1:3的比例与对照参与者进行配对匹配。最终共选取370名结直肠癌（CRC）病例及370名对照用于基因组分型。 #### NQplus研究详细信息 通过邀请瓦赫宁根、埃德、伦库姆与阿纳姆等邻近城市的随机选中居民，共招募2048名参与者。在另一邻近城市芬嫩达尔，每个家庭邀请1名个体参与NQplus研究。基线评估包括空腹静脉采血、饮食评估、体格检查、24小时尿液采集及一般情况与生活方式问卷。本研究排除179名未提供血液样本的参与者，以及有结直肠癌病史、慢性炎症性肠病或痴呆的参与者。从剩余的1869名NQplus参与者中选取对照，按照年龄与性别匹配COLON研究的结直肠癌病例。最终共选取737份对照样本用于基因组分型。