Renske de Veer (rdeveer)
Q7 Research - Screening as early diagnostics
HC 1. What is colorectal cancer?
What is colorectal cancer? → multiple levels
- Origin (cell)
- Biological background (precursors, mechanisms, molecules)
- Diagnostic procedure (presence and stage)
- Treatment options
- Outcome
Frequent kind of cancer. Second most common.
Origin (cell)
Cancer in the bowel ≠ bowel cancer
- Bowel wall: defined structure.
o Mucosal layer
o Submucosal layer
- Colorectal cancer: derived from epithelial cells in the mucosal of the bowel wall → different
crypts.
o Crypts are made from epithelial cells.
o Within crypts different kind of cells: goblet cells, enterocytes, stem cells
Biological background (precursors, mechanisms, molecules)
- Hereditary cancer syndromes
o Present in different ways
▪ Multiple polyps
▪ Familial adenomatous polyposis (APC)
• Before 18 years of age bowel removed, because they have such a
high risk of developing CRC (100%).
▪ Lynch syndrome
- Chronic inflammation
o Microenvironment of epithelial cells in the bowel is very reactive. Many ROS
produced → mutation in bowel
- Ageing
o Accumulation of mutations in all kind of cells
Inflammation and ageing: CRC
- Changing of the microenvironment
o Cytokine networks/bioactive molecules
o Cell recruitment and decreased anti-tumour response
- Reactive oxygen and nitrogen
o DNA damage
o Activation of oncogenes
o Inactivation of tumour suppressor genes
o Structural damage
- CpG island methylation
- Telomere shortening
,Renske de Veer (rdeveer)
Hallmarks of cancer
Reaction patterns
- Increased proliferation: hyperplasia.
➔ Limited space for epithelial cells. Hyperplasia results in more cells. Cells clumbs together
and form star shapes (in lumen of crypt)
- Dysplasia
o Nuclei stacked on top of each other.
o Different shaped nuclei (bigger, smaller, etc) → in nuclei nucleolus present
o Less goblet cells
o Darker stained: nuclei stained blue, more nuclei stacked on top of each other.
Low vs. High grade dysplasia
- Grade is dependent on how much the cells still resemble their normal counterparts.
o High grade: no longer individual crypts.
o Low grade: individual crypts
Precursors of CRC: The presence of precursors lesions (polyps) is a prerequisite for a population
screening program.
- Remove precursors lesions: patient will not get cancer
- Remove early cancers: patient will still have cancer, but better chance on survival.
Adenoma – Carcinoma sequence:
, Renske de Veer (rdeveer)
- Lynch syndrome (HNPCC)
o Autosomal dominant
o Genetic defects in DNA mismatch repair lead to microsatellite instability
▪ Condition of genetic hypermutability (predisposition to mutation) that
results from impaired DNA mismatch repair (MMR). Cells with abnormally
function MMR are unable to correct errors that occur during DNA replication
and consequently accumulate errors. This causes creation of novel
microsatellite (tract of repetitive DNA in which certain DNA motifs are
repeated) fragments.
o High risk on colorectal cancer (up to 80%)
▪ CRC = heterogeneous disease: each type of CRC has heterogeneous/different
futures in term of clinical response and molecular level.
o Other cancers: endometrial cancer, gastric cancer, ovarian cancer, urinary tract
cancers, small bowel cancer, glioblastoma.
o Clinical identification: Amsterdam II criteria
▪ At least three relatives must have a histological verified Lynch syndrome-
related cancer
▪ One must be first degree relative of the other two
▪ At least two successive generations must be affected
▪ At least one of the relatives with an lynch syndrome-related cancer must
have received the diagnosis before the age of 50 years.
o Patients with lynch syndrome develop tumours at younger age because they inherited
a germ line mutation from one of their parents and only need a mutation in the wild
type allele instead of 2 alleles. Hereditary cancers are causes by germline gene
mutations passed on from parents (might be lynch syndrome), whereas sporadic CRC
arises from gene damage acquired to environmental exposures, dietary factors,
hormones, normal aging, etc. Hereditary CRC often occurs earlier than sporadic CRC.
Q7 Research - Screening as early diagnostics
HC 1. What is colorectal cancer?
What is colorectal cancer? → multiple levels
- Origin (cell)
- Biological background (precursors, mechanisms, molecules)
- Diagnostic procedure (presence and stage)
- Treatment options
- Outcome
Frequent kind of cancer. Second most common.
Origin (cell)
Cancer in the bowel ≠ bowel cancer
- Bowel wall: defined structure.
o Mucosal layer
o Submucosal layer
- Colorectal cancer: derived from epithelial cells in the mucosal of the bowel wall → different
crypts.
o Crypts are made from epithelial cells.
o Within crypts different kind of cells: goblet cells, enterocytes, stem cells
Biological background (precursors, mechanisms, molecules)
- Hereditary cancer syndromes
o Present in different ways
▪ Multiple polyps
▪ Familial adenomatous polyposis (APC)
• Before 18 years of age bowel removed, because they have such a
high risk of developing CRC (100%).
▪ Lynch syndrome
- Chronic inflammation
o Microenvironment of epithelial cells in the bowel is very reactive. Many ROS
produced → mutation in bowel
- Ageing
o Accumulation of mutations in all kind of cells
Inflammation and ageing: CRC
- Changing of the microenvironment
o Cytokine networks/bioactive molecules
o Cell recruitment and decreased anti-tumour response
- Reactive oxygen and nitrogen
o DNA damage
o Activation of oncogenes
o Inactivation of tumour suppressor genes
o Structural damage
- CpG island methylation
- Telomere shortening
,Renske de Veer (rdeveer)
Hallmarks of cancer
Reaction patterns
- Increased proliferation: hyperplasia.
➔ Limited space for epithelial cells. Hyperplasia results in more cells. Cells clumbs together
and form star shapes (in lumen of crypt)
- Dysplasia
o Nuclei stacked on top of each other.
o Different shaped nuclei (bigger, smaller, etc) → in nuclei nucleolus present
o Less goblet cells
o Darker stained: nuclei stained blue, more nuclei stacked on top of each other.
Low vs. High grade dysplasia
- Grade is dependent on how much the cells still resemble their normal counterparts.
o High grade: no longer individual crypts.
o Low grade: individual crypts
Precursors of CRC: The presence of precursors lesions (polyps) is a prerequisite for a population
screening program.
- Remove precursors lesions: patient will not get cancer
- Remove early cancers: patient will still have cancer, but better chance on survival.
Adenoma – Carcinoma sequence:
, Renske de Veer (rdeveer)
- Lynch syndrome (HNPCC)
o Autosomal dominant
o Genetic defects in DNA mismatch repair lead to microsatellite instability
▪ Condition of genetic hypermutability (predisposition to mutation) that
results from impaired DNA mismatch repair (MMR). Cells with abnormally
function MMR are unable to correct errors that occur during DNA replication
and consequently accumulate errors. This causes creation of novel
microsatellite (tract of repetitive DNA in which certain DNA motifs are
repeated) fragments.
o High risk on colorectal cancer (up to 80%)
▪ CRC = heterogeneous disease: each type of CRC has heterogeneous/different
futures in term of clinical response and molecular level.
o Other cancers: endometrial cancer, gastric cancer, ovarian cancer, urinary tract
cancers, small bowel cancer, glioblastoma.
o Clinical identification: Amsterdam II criteria
▪ At least three relatives must have a histological verified Lynch syndrome-
related cancer
▪ One must be first degree relative of the other two
▪ At least two successive generations must be affected
▪ At least one of the relatives with an lynch syndrome-related cancer must
have received the diagnosis before the age of 50 years.
o Patients with lynch syndrome develop tumours at younger age because they inherited
a germ line mutation from one of their parents and only need a mutation in the wild
type allele instead of 2 alleles. Hereditary cancers are causes by germline gene
mutations passed on from parents (might be lynch syndrome), whereas sporadic CRC
arises from gene damage acquired to environmental exposures, dietary factors,
hormones, normal aging, etc. Hereditary CRC often occurs earlier than sporadic CRC.
