(1) Bioresource Overview
The Biobank Hereditary colorectal cancer (CRC) was established in 2009 with the aim to enable researchers to gain a better insight into the genetic factors contributing to the development of CRC, and ultimately, disease prevention. In addition, future research will improve the quality and efficiency of care of individuals with hereditary CRC.
Participants are 1) diagnosed with a germline mutation that causes CRC and/or Polyposis (e.g. APC, MLH1, MSH2, MSH6 or MUTYH) (‘affected’) or 2) are at an increased risk of hereditary CRC and/or Polyposis (‘unaffected’). Patients diagnosed with CRC before the age of 70 years, diagnosed with an adenoma before the age of 40 years, diagnosed with cumulative more than 10 adenomas, diagnosed with polyposis or diagnosed with CRC and/or adenoma with a germline mutation present in the family for hereditary CRC and/or Polyposis are considered to have an increased risk of hereditary CRC and/or Polyposis. Both clinical data (demographic data, details on medical and family history plus endoscopy and surgery, results of microsatellite instability and molecular genetic tests) and biomaterial (DNA, plasma and serum plus both unaffected colorectal tissue and affected colorectal tissue, i.e. adenoma or carcinoma) are collected in a standardized way.
The Biobank Hereditary CRC is part of the Parelsnoer Institute (PSI; ), which is a unique nationally representative biobanking partnership between the eight University Medical Centers (UMCs) in the Netherlands. As such the Biobank Hereditary CRC is embedded in a mature national infrastructure for biobanks.
Clinical biobank: biological samples and associated data, clinical data.
All eight University Medical Centers across the Netherlands: Academic Medical Center (Amsterdam), Erasmus Medical Center (Rotterdam), Leiden University Medical Center, Maastricht University Medical Center, Radboud University Medical Center (Nijmegen), University Medical Center Groningen, University Medical Center Utrecht, VU University Medical Center (Amsterdam).
Northern boundary: +53.4647366.
Southern boundary: +50.757197.
Eastern boundary: +7.222824.
Western boundary: +3.364563.
Start data: 2009. End date: not applicable. The intention is to include patients as long as possible, which implies that biomaterial and associated data will be stored without time limitations.
Temporal coverage for accessibility
The Biobank Hereditary CRC has not indicated a date when it has to be destroyed.
Eligible individuals for the Biobank Hereditary CRC are included at three different departments: the departments of Human Genetics, Surgery or Gastroenterology. Individuals are considered to be eligible when they have been diagnosed with a germline mutation that causes CRC and/or Polyposis, diagnosed with CRC before the age of 70 years or with an adenoma before the age of 40 years, diagnosed with cumulative more than 10 adenomas, diagnosed with polyposis, diagnosed with CRC and/or adenoma with a germline mutation present in the family for hereditary CRC and/or Polyposis. Patients are recruited and consented in one of the participating UMC’s by a clinician or a research nurse. Standard operating procedures (SOPs) are in place to cover the consent and withdrawal process.
Each department collects biomaterials in a uniform way and in a routine clinical care setting.
Tissue from a surgical procedure or colonoscopy will be stored as frozen or Formalin-Fixed Paraffin-Embedded (FFPE) material. Tissue samples are processed by trained and certified staff through the UMC histology departments and only surplus material is passed to the Biobank Hereditary CRC. Some participants will visit the UMC more often, e.g. for endoscopy surveillance. For these participants, follow-up data will be collected and samples of plasma, serum and tissue will be stored with a maximum of twice a year in order to reduce the burden. This will be the first two visits in a year because it is not possible to determine in advance which event is important.
Sample handling and storage are based on SOPs. These procedures were established by PSI to ensure standardized sample collection and handling, and to guarantee a collection of samples of high and reproducible quality . Deviations from the SOPs are recorded using predefined categories which include: issues with haemolytic, lipemic, icteric, wrong tube, incorrect volume collected, storage temperature deviation, longer storage time, incorrect mixing/homogenization, different centrifugation process, storage problem or other deviation as free text. Figure 1 shows the schematic workflow of the Biobank Hereditary CRC. The biomaterial is stored at each participating UMC. Note: this is a general workflow that can deviate in the different participating UMCs, depending on the local workflows.
Table 1 gives an overview of procedures for collecting, processing and storing of samples defined in the Biobank Hereditary CRC’s biomaterial protocol.
|Sample||Volume/number||Processing||Time between sampling and storage||Aliquoting||Storage|
|DNA (blood)||6 ml EDTA blood||Standard DNA isolation from EDTA in clinical routine of the Department of Human Genetics||Within 4 weeks (4°C) or 3 months (<–20°C)||Stock solution, after first issuance: normalized fraction 100 ng/μL||–20°C|
|Serum||10 ml, addition of a clot activator||2,000 × g at room temperature for 10 minutes||Within 2–4 hours||Maximum of six aliquots (0.5 ml)||–80°C|
|EDTA plasma||10 ml||2,000 × g at room temperature for 10 minutes||Within 2–4 hours||Maximum of six aliquots (0.5 ml)||–80°C|
|Fresh frozen tissue||Sample of affected and unaffected tissue||Immediately frozen after collecting the sample||Immediate||0.5 cm3 samples||–80°C|
|FFPE tissue1||Sample of affected and unaffected tissue||Immediately stored in formalin after collecting the sample (0.5 cm3), afterwards embedded in paraffin||Immediate fixation||0.5 cm3 samples||Room temperature|
Type of long-term preservation
See Table 1.
See Table 1.
Shipping temperature from patient/source to preservation or research use
Body fluids (DNA, plasma, serum) from the clinical departments are transferred by the internal clinical transport service of each UMC to the Front Office of the laboratory that is responsible for the sample handling.
Fresh frozen and FFPE tissue are directly transferred from the operating rooms to the Department of Pathology by the internal clinical transport service of each UMC. The tissue should be sent in a good leak-proof, unadorned container with formalin. The volume of formalin should be at least twice as large as the tissue fragment. Until transport, tissue can best be stored at 4°C (refrigerator) or briefly at room temperature and not in (melting) ice.
Shipping temperature from storage to research use
Body fluids, or materials and fresh frozen tissue samples are shipped on an excess of dry ice (–80°C) and FFPE samples at room temperature. Shipment is carried out by various certified courier services. At the moment, data loggers are not used. However, each confirmation of receipt of a shipment attests that sufficient dry ice was still present in the package.
Quality assurance measures
The sample handling is embedded in the quality management system of all cooperating UMC’s . Process control is based on SOPs that cover all phases of biobanking: collection, pre-analysis, registration, processing and storage of the samples.
Source of associated data
For the Biobank Hereditary CRC a minimal dataset was defined. This dataset comprises patient information collected in the context of routine daily clinical practice (Table 2). At baseline clinical data is collected on demographic data, details on medical and family history plus endoscopy and surgery, results of microsatellite instability and molecular genetic tests. During the follow-up, data is obtained on the treatment of the patient. Furthermore, in order to facilitate complete follow-up information on all included patients, connections to existing medical registries are actively sought (e.g. links to registries for vital status, cause of death, cancer diagnoses and pathology records).
|General information of the patient||Identifier
Date of birth
Date of inclusion
Date of death
Autopsy has been performed
Cause of death
|Information on medical history of the patient||Date of consult
No previous surgery or admission to a hospital
CRC – date of diagnosis
Diagnosis of CRC – based on complaints
Diagnosis of CRC – based on surveillance CRC
Year of start surveillance CRC
Type of surveillance used at diagnosis of CRC
Date of penultimate surveillance
Additional remarks regarding CRC in general
Adenomas – date of diagnosis
Colitis Ulcerosa/M. Crohn
Colitis Ulcerosa/M. Crohn – date of diagnosis
Date of first visit to a hospital
Above 10 adenomas (cumulative)
Date of diagnosis of 10th adenoma
Above 10 polyps unlike adenoma
Date of diagnosis of 10th polyp unlike adenoma
Cancer unlike CRC
Cancer unlike CRC – date of diagnosis
Additional remarks regarding medical history
Type of tobacco
Amount of cigarettes per day
Year of start smoking
Last year of stop smoking
|Physical examination||Height (cm)
Current weight (kg)
Weight at endoscopy (kg)
Weight at surgery (kg)
Highest weight (excl. pregnancy – kg)
Year of highest weight
|Information on first degree family members of the patient||Relationship between first degree family member and patient
Year of birth of first degree family member
Date of inquiry of medical history of first degree family member
Medical history of first degree family member
Age at diagnosis of first degree family member
Date of death of first degree family member
First degree family member participant of biobank
|Genetic testing||Genetic testing started in family
Year of start genetic testing
Germline mutation present (patient or family)
Gene with germline mutation
Name of germline mutation
Is the patient a mutation carrier
Year of diagnosis germline mutation – patient
Molecular diagnostics on colorectal related material
Microsatellite instability present
Additional remarks regarding molecular diagnostics – other
Date of endoscopy
Type of endoscopy
Indication for endoscopy
Total number of polyps (endoscopy)
Location of endoscopy
Number of polyps per location (endoscopy)
|Lesion – endoscopy (>10 polyps, registration of additional information)||Polyp number
Location of lesion
Distance between lesion and anus (cm – stretched endoscope)
Size of lesion (mm – endoscopy)
Form of lesion
Type of lesion (macroscopic – endoscopy)
Radically removed (macroscopic – endoscopy)
Treatment of lesion (endoscopy)
Date of surgery
Type of surgery
Location of the tumor
Location of distant metastasis
Stoma – temporary or permanent
Date of start preoperative radiotherapy
Total dose of preoperative radiotherapy (gray – cumulative)
Total of preoperative radiotherapy fractions
Type of preoperative chemotherapy
Date of start preoperative chemotherapy
Total of preoperative chemotherapy cycles
Tumor size (pT)
Number of removed lymph nodes – surgery
Number of positive lymph nodes – surgery
Number of removed polyps/adenomas – surgery
Location of regional metastasis
Location per adenoma (surgery)
Number of adenomas (surgery)
Size of largest adenoma (mm – surgery)
Location largest adenoma (surgery)
Hyperplastic polyps (surgery)
Number of hyperplastic polyps (surgery)
Additional remarks regarding tissues removed at surgery
Type of removed material – endoscopy
Type of lesion
Type of adenoma
Type of dysplasia (adenoma)
|Data on biomaterial||Collecting time
Amount of tissue
Other SOP deviation
The Biobank Hereditary CRC guarantees the privacy of the participants, because both biomaterial and the associated clinical data are stored using unique codes.
As described by Manniën et al., the information supplied by each UMC is periodically uploaded, after validation, to the central database of PSI for storage on a national level . During the upload of data to central database, a Trusted Third Party encrypts identifiers of each UMC.
In 2009, the local Research Ethics Committees (RECs) of all UMCs have approved the initiation of the Biobank Hereditary CRC. Each research proposal that includes the use of biomaterial and/or clinical data of the Biobank Hereditary CRC must be submitted to the scientific review committee of the Biobank Hereditary CRC. This committee will decide whether a protocol is relevant and valid. As a next step, the research proposal has to be approved by the REC or a formal Institutional Review Board (IRB). These committees will assess whether the study objective fits the scope of the Biobank Hereditary CRC and its informed consent procedure.
Eligible patients are invited to participate in the Biobank Hereditary CRC, and sign the informed consent after understanding the goals of the biobank. SOPs are in place to cover the consent and withdrawal process.
Geographical: the Biobank Hereditary CRC collects biomaterial primarily collected at UMCs, tertiary care hospitals. Only patients who provided written informed consent are included. Participants may withdraw their consent at all times.
(3) Bioresource description
The Biobank Hereditary CRC.
The Biobank Hereditary CRC.
All eight UMCs across the Netherlands participate in PSI:
- – Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- – Erasmus Medical Center, ’s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
- – Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
- – Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands
- – Radboud university medical center, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands
- – University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
- – University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands
- – VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
Peggy Manders, Geert Grooteplein-Zuid 10, 6525 GA Nijmegen, The Netherlands.
The Biobank Hereditary CRC Radboud Biobank is a collaborative clinical biobank. It stores biomaterials (see Table 1) and clinical data (Table 2) of individuals with an increased risk of hereditary CRC and/or Polyposis or diagnosed with a gene mutation which causes CRC and/or Polyposis and achieves almost total population coverage because the larger part is seen in a UMC.
Type of sampling
The Biobank Hereditary CRC is a biobank that combines both ‘affected’ individuals diagnosed with a gene mutation that predisposes to CRC and/or Polyposis (e.g. APC, MLH1, MSH2, MSH6 or MUTYH) and ‘unaffected’ individuals at increased risk of hereditary CRC and/or Polyposis (i.e diagnosed with a CRC or adenoma at a relatively young age).
See Table 3.
|Patient Category1||Description||Number of included participants1|
|1||Patient with CRC diagnosed before the age of 70 years||1,120|
|2||Patient with CRC with a germline mutation present in the family for hereditary CRC or polyposis||97|
|3||Patient with an adenoma diagnosed before the age of 40 years||167|
|4||Patient with an adenoma with a germline mutation present in the family for hereditary CRC or polyposis||214|
|5||Patient with polyposis (FAP, AFAP, MAP, juvenile polyposis)||243|
|6||Patient with cumulative more than 10 adenomas||178|
|7||Patient with other polyposis syndrome than described in category 5 (e.g. Peutz Jeghers, PTEN Hamartome Tumour Syndrome)||133|
|8||Patient with CRC and a germline mutation for hereditary CRC or polyposis||141|
|9||Healthy individual with a germline mutation for hereditary CRC or polyposis||374|
|10||Patient with an adenoma and a germline mutation for hereditary CRC or polyposis||211|
Disease status of patients/source
See Table 3.
Clinical characteristics of patients/source
A full clinical characterization, including demographic data, details on medical and family history plus endoscopy and surgery, results of microsatellite instability and molecular genetic tests and follow-up is specified for the Biobank Hereditary CRC (Table 2).
Vital state of patients/source
All patients are alive at inclusion.
Size of the bioresource
Currently, the Biobank Hereditary CRC contains different biomaterials (e.g. DNA, plasma, serum and/or tissue) from 1,967 participants. The current number of included patients per patient category is shown in Table 3.
Clinical diagnosis of patients/source
See Table 3.
Colorectal carcinoma and adenoma.
The Biobank Hereditary CRC does not collect control samples from individuals without a proven CRC and/or Polyposis related germline mutation or who are not at an increased risk of hereditary CRC and/or Polyposis.
Table 1 summarizes the variety of biomaterials that can be collected per participant of the Biobank Hereditary CRC. However, the specific collection of the biomaterials depends on the patient category, e.g. tissue will only be collected of the patients who have been diagnosed with CRC and were surgically treated in one of the participating UMCs.
Biomaterial and the matching clinical data are currently available.
Scientific researchers, who are not necessarily linked to the Biobank Hereditary CRC, but who are working in the field of hereditary CRC are invited to submit their research proposals. In the catalog of PSI  a researcher can identify which items are collected by the latter biobank. Each new study proposal should be sent to the coordinator of the Biobank Hereditary CRC (i.e. currently dr. P. Manders; Radboudumc, The Netherlands). The coordinator will submit the proposal to the scientific review committee of the Biobank Hereditary CRC. This committee, which consists of one member of each participating UMC, will review every application on the following criteria: the anticipated significance of the research for hereditary forms of CRC and thus the patients included in the Biobank Hereditary CRC, plus scientific quality, novelty, feasibility and the suitability. The review process for rare patient groups is less strict for requests for data usage than requests for biomaterial groups, because of the finite nature of the biomaterial. The researcher will be informed in writing about the decision of the latter committee by the coordinator. As a next step, the research proposal has to be approved by the REC or a formal IRB. These committees will assess whether the study objective fits the scope of the Biobank Hereditary CRC and its informed consent procedure. The aim of the Biobank Hereditary CRC is to make the whole issuance process as simple and transparent as possible for researchers. Therefore, the coordinator of the Biobank Hereditary CRC acts as a contact for researchers throughout the complete issuance process.
Costs vary depending on the type and amount of samples. An economic quotation is sent covering shipping costs and partially costs for biobanking-related services (sample handling, consumables) .
(4) Reuse potential
Biomaterial and clinical data are provided to researchers on a non-exclusive basis. Therefore samples from the same participant may be used in several different projects. However, each research project must be approved by the scientific review committee of the Biobank Hereditary CRC and by the REC or a formal IRB. A prerequisite for the delivery of biomaterial and clinical data is two-way data sharing. Which implies that new information becomes available from scientific analyses, will be added to the Biobank Hereditary CRC database.