Familial Colorectal Cancer Flashcards
What are common symptoms of Lynch syndrome
Uncontrolled inflammatory bowel disease - Crohn’s, UC and diverticulitis
What lesion precedes a carcinoma
Adenoma
How do adenomas develop into carcinomas
Benign polyps - small, capsulated, non-invasive
Grows into an adenoma
These adenomas can become carcinomas (cancerous) by spreading into the muscle layer, serosa, nearby lymph nodes and then metastasise
What are the 2 major molecular events leading to colorectal cancer
Chromosomal instability (85%) e.g. APC gene
Microsatellite instability - lynch syndrome
Instability = higher chance of further mutations due to loss in cell QC mechanisms
What is lynch syndrome
AD cause of bowel and some other cancers
Caused by pathogenic variants in genes central to the DNA mismatch repair pathway (MLH1, MSH2, MSH6, PMS2 and EPCAM)
Also known as HNPCC – hereditary non polyposis coli
What are the type of genes involved in lynch syndrome
Mismatch repair genes
What do mismatch repair proteins do
They work in pairs and recruits EXO1 which chops off the mutate strand
Different mutations in different genes have different implications
Dimers = MLH1 and PMS2 and MSH2 and MSH6
What are the lynch syndrome gene dimer pairs
Dimers = MLH1 and PMS2 and MSH2 and MSH6
Why do MMR mutations increase cancer risk
MMR mutations increased cancer risk
Reduce ability of DNA repair
Results in build-up of mutations that can lead to cancer
What of the two major molecular events leading to cancer causes lynch syndrome
Lynch syndrome dominant microsatellite regions of DNA are susceptible to DNA mismatch
Loss of MMR protein function causes microsatellite instability, a key mutational signature of Lynch syndrome cancers
What are the major lynch syndrome related cancers
Major = colorectal, endometrial and ovarian, abdominal
What criteria is used to identify families likely to have lunch syndrome
Amsterdam II Criteria
What is the Amsterdam II criteria
Helps identify families that are likely to have lynch syndrome
3, 2, 1 rule
3 or more relatives with a lynch related cancer
2 or more successive generations involved
1 or more relatives diagnosed under 50 years
What are other
Muir-Torre syndrome (MRTES) - seen in families with skin lesions, sebaceous adenomas + bowel cancer
Mismatch repair cancer syndrome (MMRCS1/CMMRDS)
What is Mismatch repair cancer syndrome (MMRCS1/CMMRDS)
Normally you only see one alteration in one copy of the gene but in this situation, it is two copies
Can occur randomly but often in consanguineous relationships
Found in children with multiple cancers , can see brain cancers and some bowel cancers in history
When is tumour tissue testing undertaken
• Undertook in families with limited history, Amsterdam II criteria not fully fulfilled but still needs to be investigated
What is tumour tissue testing with lynch syndrome
MSI testing - PCR looks for microsatellite instability (high, low, normal, abnormal)
Mismatch repair immunohistochemistry - staining looking for presence or absence
Loss of a dimer suggests lynch syndrome
However there are other causes including somatic changes that are not inherited
MLH1 promoter hypermethylation(BRAF V600E) - older endometrial and bowel cancers
Biallelic somatic mutation
How is lynch syndrome managed
Management depends on the gene that is mutated, as each have significantly different risks
MLH1 has a greater increased risk of colorectal cancer than PMS2 for example
What is the screening procedure for lynch syndrome - specifically for MLH1 management
Colorectal screening - 2-yearly colonoscopy from ages 25-75, review at 75
Gastric screening - helicobacter pylori one-off screening
Cervical screening - as part of NHS screening programme, can detect SOME womb cancers
What is the risk reducing surgery recommendations for lynch syndrome - specifically MLH1 management
Offer risk-reducing hysterectomy with BSO, once childbearing is complete - no earlier than 35-40 years (risks and benefits to be discussed)
Not recommended for PMS2 as there is only a population risk
HRT should be offered until 51 in women who have not had a ER positive breast cancer
What are the chemoprevention options for lynch syndrome - specifically MLH1 management
Discuss pros and cons of aspirin chemoprevention from age 25-65 (GP to prescribe), 150mg OD if <70kg or 300mg if >70kg
What are the cancer management options for lynch syndrome
Targeted therapies may be available as a treatment option for certain cancer types (immune checkpoint inhibitors e.g. pembrolizumab)
Surgical management of colon cancer - discussion regarding pros and cons of segmental V extensive resection may be appropriate
Adjuvant 5-FU chemotherapy may not be appropriate for patients with Dukes’ B colorectal-cancers
What is a potential targeted therapy for lynch syndrome
Pembrolizumab
What is a polyp
Polyp = an overgrowth of tissue projecting from a mucous membrane, usually benign
Where are polyps commonly found
Commonly found in the colon, stomach, sinuses, bladder, uterus
What are inherited polyposis syndromes
Inherited polyposis syndromes are caused by pathogenic genetic variants leading to increased polyp formation
What are the two structures of polyps
Polyps can be pedunculated or sessile
Pedunculated polyps have a stalk structure which are easier to remove
As its further away from the basal layers, it takes longer for cancer to invade
Sessile polyps are flat and more difficult to remove, and are closer to the basal layers
How do you investigate polyps
Type, size, amount
Identified with colonoscopy and an indigo dye
What are the classifications of polyps
Adenomatous - high risk of becoming cancerous and dysplastic
Hyperplastic-serrated - small, typically benign and not dysplastic
Inflammatory - typically benign
Hamartomatous - inherited polyposis syndromes
What is the difference between hyperplastic-serrated polyps and serrated adenomas
Hyperplastic-serrated - small, typically benign and not dysplastic
Serrated adenomas - hyperplastic with dysplasia
What are the types of adenomatous polyps
Tubular adenoma, tubulovillous adenoma and villous adenoma
What polyps are hamartomatous
Juvenile polyps, Peutz-Jegher Syndrome polyps, and polyps seen in Cowden syndrome
How does size relate to malignancy in regards to polyps
The larger a polyp, the greater the risk of harbouring dysplastic cells and developing into colorectal cancer
That risk significantly increases if the polyp is greater than 10mm (1cm)
Polyps that are >2cm have 40% risk of developing into cancer
What is a high risk sign of an inherited polyposis syndrome
I a young patient present (<50 years) with lots of polyps this may indicate an inherited polyposis syndrome
What genes are involved in inherited polyposis syndromes
They are often associated with tumour suppressor genes, such as the APC gene involved with Familial adenomatous polyposis (FAP)
How are adenomatous polyps screened
Faecal occult blood test - 2-yearly test from 60 years
1-2% abnormal = colonoscopy, of these 10% have colorectal cancer
What are the risk factors of adenomatous polyps
Age >50
Gender - higher in males
Ethnicity - higher in African/Caribbean populations
Family history - heritable factors account for 35% of CRC and 30% of UK population have a family history
Clinical and molecular features of polyps
What are the surveillance options for adenomatous polyps
Sigmoidoscopy and colonoscopy
What is the chemoprevention options for adenomatous polyps
Aspirin
Are adenomatous polyps benign or malignant
Classified as neoplastic polyps - start oof benign but can become malignant
How long does it take an adenomatous polyp to progress into cancer
5-20 years
What are the three histological types of adenomatous polyps
Three types with increasing malignant potential
Tubular (TA) - usually pedunculated
Tubulovillous (TVA)
Villous (VA) which can then form an adenocarcinoma - cauliflower like, with tree-branches
What is the APC gene
85% of all somatic CRC are caused by somatic variants in the adenomatous polyposis coli (APC) gene
This is a tumour suppressor gene, found in the long arm of chromosome 5 (5q22)
It is a multidomain protein that has roles in cell regulation and slows down cell division
The first mutation breaks down these properties so cell proliferation spreads out of control
What are the stages of APC mutation
Normal epithelia > APC mutation > dysplastic epithelia > K-ras mutation > ademnoma > p53 mutation > carcinoma > metastatic cancer
Throughout these steps the polyp grows
What is Knudson’s two hit hypothesis in relation to APC mutations
If APC mutation is inherited, it’ll still require a secondary hit, which occurs when polyps grow and mutate
Having the inherited gene means that the process is brought forward by approximately 30 years
An example is familial adenomatous polyposis syndrome (FAP)
What is the inheritance pattern of FAP
It is an autosomal dominant mutation, with De novo mutation rate being 30%
APC gene mutations are 100% penetrant
Where are tumours found in FAP
Extracolonic tumours - upper GI, desmoids, osteoma, thyroid, liver and brain, lipomas, epidermoid cysts
Other extra intestinal features
CHRPE (congenital hypertrophy of the retinal epithelium) = seen in 70-80% of cases
Supernumerary teeth, multiple jaw osteomas and odontoma
What is the management of FAP
Genetic counselling - predictive genetic APC testing for FDR
Surveillance - colonoscopy.
Endoscopy, MRI
Surgery - elective prophylactic colectomy
How does the site of APC mutation influence gene expression/symptoms
Exon 15 comprises 75% of the coding sequence of the gene thus is a common target for mutations
Exon 9 = CHRPE
5’ and 3’ = mild colonic phenotype, also known as attenuated FAP
What is attenuated FAP caused by
5’, exon 9, 3’ and whole gene deletions in APC gene
What is the difference between FAP and attenuated FAP
Phenotype = much fewer polyps
10 to less than 100 adenomas (averaging 30)
Frequent right-sided distribution of polyps (ascending side)
Later onset of adenomas and carcinomas (mean age of diagnosis is <50 years)
70% develop colorectal cancer by 80
Upper GI findings and duodenal cancer risks similar to classical FAP
Desmoid tumours associated with 3’ mutations
What is MUTYH associated polyposis
Multiple adenomatous colonic polyps - phenotypically indistinguishable from FAP/AFAP
What is the inheritance pattern of MUTYH mutation
Autosomal recessive pattern of inheritance
Thus FAP can be differentiated by inheritance
How can you identify the difference between multiple adenomatous colonic polyps and FAP
Differentiated by inheritance
FAP = AD MACP = AR
What is tested on a polyp gene panel
APC MUTYH POLD1 and POLE AD inheritance 10-100 adenomas Some hyperplastic polyps Too few families to define full phenotype
What are sessile serrated polyps
Sessile Serrated polyps tend to lie on folds and can be obscured by surface mucin when small, so are difficult to detect on endoscopy
Are sessile serrated polyps dysplastic
Sessile serrated polyps are not usually dysplastic but can undergo dysplasia
What are traditional serrated adenomas
These are rarer to find than sessile serrated polyps but have a greater risk of becoming cancerous
These can be recognised by ‘ectopic crypts’ which come off from the main crypts (under microscope)
What is the cause of serrated polyposis syndrome
While somatic pathway understood a germline cause for serrated polyposis has yet to be found
What is the diagnostic criteria for serrated polyposis syndrome
As there is not a known genetic cause, the WHO have created a diagnostic criteria
> 5 serrated lesions/polyps proximal to the rectum, all >5mm in size, with at least 2 being >10mm in size
> 20 serrated lesions/polyps of any size distributed throughout the large bowel, with >5 being proximal to the rectum
What is the surveillance options for serrated polyposis syndrome
Depends on the size and the altered pathology
Surveillance after one year if…
There is advanced SP (TS and/or >10mm and/or containing dysplasia)
>1 advanced adenoma (>10mm and/or high-grade dysplasia and/or >25% villous)
>5 SSL (irrespective of size) and/or adenomas (irrespective of size) and/or HPs >5mm
Surgery needed
If none of the above, surveillance after 2 years
What are hamartomatous polyps
Tumour-like growths with a mix of tissues - connective tissue, mucus filled glands, retention cysts
Are hamartomatous polyps sessile or pedunculated
Macroscopically they are usually pedunculated, smooth and vascularised
What is the size and histology of hamartomatous polyps
Vary in size, and have characteristic histology depending if they are Peutz Jeghers polyps or juvenile
Where do hamartomatous polyps usually occur
Can occur anywhere in the GI tract - intestinal or extra-intestinal
Are hamartomatous polyps neoplastic
They are mainly non-neoplastic
Sporadic hamartomatous polyps are usually solitary and have a very low malignant potential
Multiple polyps may occur as part of a polyposis syndrome, which increases the risk of cancer due to co-occurrence with adenomatous polyps
Is family genetic testing required when identifying hamartomatous polyps
Family genetic testing may be required
Inherited polyposis syndromes include Peutz Jeghers Syndrome, Juvenile Polyposis Syndrome and PTEN Hamartoma Tumour Syndromes
What is Peutz Jeghers Syndrome
AD syndrome caused by variants STK11 gene on chromosome 19, p-arm
70-80% = germline variants, 25% De novo
What are the clinical features of Peutz Jeghers syndrome
Polyps throughout the GI tract - typically in the small intestine
Freckling on lips, mucosa, hands and feet from early age - may fade with age, making it less obvious
What are the complications of Peutz Jeghers syndrome
Intussusception - one part of the intestine sliding int the other - this can result in bowel obstruction
Anaemia, chronic bleeding
Increased risk of cancer - colorectal, gastric, pancreatic and ovarian
How is Peutz Jeghers syndrome diagnosed
Clinical features
Endoscopy
Histological analysis
STK11 testing confirms diagnosis and aids testing in family members
How is Peutz Jeghers syndrome managed
GI tract screening - endoscopy, removal of large polyps
Breast screening
Cervical screening
What is juvenile polyposis syndrome
AD caused by various gene variants involved in TBF BETA signalling pathway
What are the genes involved in juvenile polyposis syndrome
SMAD4 - chromosome 18, found in up to 50% of patients
BMPR1A - chromosome 10
ENG1 - chromosome 9
What are the clinical features of juvenile polyposis syndrome
Multiple juvenile polyps in the lower bowel - numbers vary
These are benign harmatomatous polyps, covered in mucus filled cysts
Congenital abnormalities (20%) - hydrocephaly’s and cardiac lesions
How is juvenile polyposis syndromes diagnosed
One of the following criteria
> 5 colorectal polyps
Multiple juvenile polyps of upper and lower GI tract
Any number of juvenile polyps and a family history
How is juvenile polyposis syndromes managed
Endoscopy from age 15 or earlier if symptoms present
What are PTEN hamartoma tumour syndromes
AD caused by PTEN mutations found on chromosome 10, q-arm
What is PTEN
This is a tumour suppressor gene involved in the mTOR pathway
Ubiquitously expressed protein
PTEN pathogenic variants identified in 85% of PHTS patients
What are the PTEN syndromes
Cowden syndrome
GI polyps
Risk of malignancy
Banayan-Riley-Ruvalcaba syndrome
Colonic and ileal polyps
Lhermitte-Duclos disease
Cerebella harmatomatous overgrowth
What is Cowden syndrome
Few to 100 harmatomatous polyps in GI tract in ~95%
Mainly harmatomatous, also ganglioneuromatous, adenomatous or lymphoid
What are the features of Cowden syndrome
Skin trichilemmomas from adolescence
Thyroid disorders - goitre
Uterine fibroids
Fibrocystic breast
Macrocephaly (84%)
What are the complications with Cowden syndrome
Increased risk of cancer - thyroid, endometrial, breast
How is Cowden syndrome diagnosed
Clincial features and genetics
