Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Clinical Applications of Genomics in Rare Disease and Cancer > Familial Colorectal Cancer > Flashcards

Familial Colorectal Cancer Flashcards

(84 cards)

Start Studying
1
Q

What are common symptoms of Lynch syndrome

A

Uncontrolled inflammatory bowel disease - Crohn’s, UC and diverticulitis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What lesion precedes a carcinoma

A

Adenoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

How do adenomas develop into carcinomas

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the 2 major molecular events leading to colorectal cancer

A

Chromosomal instability (85%) e.g. APC gene

Microsatellite instability - lynch syndrome

Instability = higher chance of further mutations due to loss in cell QC mechanisms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is lynch syndrome

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the type of genes involved in lynch syndrome

A

Mismatch repair genes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What do mismatch repair proteins do

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the lynch syndrome gene dimer pairs

A

Dimers = MLH1 and PMS2 and MSH2 and MSH6

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Why do MMR mutations increase cancer risk

A

MMR mutations increased cancer risk

Reduce ability of DNA repair

Results in build-up of mutations that can lead to cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What of the two major molecular events leading to cancer causes lynch syndrome

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the major lynch syndrome related cancers

A

Major = colorectal, endometrial and ovarian, abdominal

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What criteria is used to identify families likely to have lunch syndrome

A

Amsterdam II Criteria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the Amsterdam II criteria

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are other

A

Muir-Torre syndrome (MRTES) - seen in families with skin lesions, sebaceous adenomas + bowel cancer

Mismatch repair cancer syndrome (MMRCS1/CMMRDS)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is Mismatch repair cancer syndrome (MMRCS1/CMMRDS)

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

When is tumour tissue testing undertaken

A

• Undertook in families with limited history, Amsterdam II criteria not fully fulfilled but still needs to be investigated

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is tumour tissue testing with lynch syndrome

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How is lynch syndrome managed

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is the screening procedure for lynch syndrome - specifically for MLH1 management

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is the risk reducing surgery recommendations for lynch syndrome - specifically MLH1 management

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What are the chemoprevention options for lynch syndrome - specifically MLH1 management

A

Discuss pros and cons of aspirin chemoprevention from age 25-65 (GP to prescribe), 150mg OD if <70kg or 300mg if >70kg

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are the cancer management options for lynch syndrome

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What is a potential targeted therapy for lynch syndrome

A

Pembrolizumab

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is a polyp

A

Polyp = an overgrowth of tissue projecting from a mucous membrane, usually benign

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Where are polyps commonly found
Commonly found in the colon, stomach, sinuses, bladder, uterus
26
What are inherited polyposis syndromes
Inherited polyposis syndromes are caused by pathogenic genetic variants leading to increased polyp formation
27
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
28
How do you investigate polyps
Type, size, amount Identified with colonoscopy and an indigo dye
29
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
30
What is the difference between hyperplastic-serrated polyps and serrated adenomas
Hyperplastic-serrated - small, typically benign and not dysplastic Serrated adenomas - hyperplastic with dysplasia
31
What are the types of adenomatous polyps
Tubular adenoma, tubulovillous adenoma and villous adenoma
32
What polyps are hamartomatous
Juvenile polyps, Peutz-Jegher Syndrome polyps, and polyps seen in Cowden syndrome
33
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
34
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
35
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)
36
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
37
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
38
What are the surveillance options for adenomatous polyps
Sigmoidoscopy and colonoscopy
39
What is the chemoprevention options for adenomatous polyps
Aspirin
40
Are adenomatous polyps benign or malignant
Classified as neoplastic polyps - start oof benign but can become malignant
41
How long does it take an adenomatous polyp to progress into cancer
5-20 years
42
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
43
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
44
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
45
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)
46
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
47
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
48
What is the management of FAP
Genetic counselling - predictive genetic APC testing for FDR Surveillance - colonoscopy. Endoscopy, MRI Surgery - elective prophylactic colectomy
49
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
50
What is attenuated FAP caused by
5', exon 9, 3' and whole gene deletions in APC gene
51
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
52
What is MUTYH associated polyposis
Multiple adenomatous colonic polyps - phenotypically indistinguishable from FAP/AFAP
53
What is the inheritance pattern of MUTYH mutation
Autosomal recessive pattern of inheritance Thus FAP can be differentiated by inheritance
54
How can you identify the difference between multiple adenomatous colonic polyps and FAP
Differentiated by inheritance ``` FAP = AD MACP = AR ```
55
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 ```
56
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
57
Are sessile serrated polyps dysplastic
Sessile serrated polyps are not usually dysplastic but can undergo dysplasia
58
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)
59
What is the cause of serrated polyposis syndrome
While somatic pathway understood a germline cause for serrated polyposis has yet to be found
60
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
61
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
62
What are hamartomatous polyps
Tumour-like growths with a mix of tissues - connective tissue, mucus filled glands, retention cysts
63
Are hamartomatous polyps sessile or pedunculated
Macroscopically they are usually pedunculated, smooth and vascularised
64
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
65
Where do hamartomatous polyps usually occur
Can occur anywhere in the GI tract - intestinal or extra-intestinal
66
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
67
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
68
What is Peutz Jeghers Syndrome
AD syndrome caused by variants STK11 gene on chromosome 19, p-arm 70-80% = germline variants, 25% De novo
69
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
70
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
71
How is Peutz Jeghers syndrome diagnosed
Clinical features Endoscopy Histological analysis STK11 testing confirms diagnosis and aids testing in family members
72
How is Peutz Jeghers syndrome managed
GI tract screening - endoscopy, removal of large polyps Breast screening Cervical screening
73
What is juvenile polyposis syndrome
AD caused by various gene variants involved in TBF BETA signalling pathway
74
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
75
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
76
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
77
How is juvenile polyposis syndromes managed
Endoscopy from age 15 or earlier if symptoms present
78
What are PTEN hamartoma tumour syndromes
AD caused by PTEN mutations found on chromosome 10, q-arm
79
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
80
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
81
What is Cowden syndrome
Few to 100 harmatomatous polyps in GI tract in ~95% Mainly harmatomatous, also ganglioneuromatous, adenomatous or lymphoid
82
What are the features of Cowden syndrome
Skin trichilemmomas from adolescence Thyroid disorders - goitre Uterine fibroids Fibrocystic breast Macrocephaly (84%)
83
What are the complications with Cowden syndrome
Increased risk of cancer - thyroid, endometrial, breast
84
How is Cowden syndrome diagnosed
Clincial features and genetics

Clinical Applications of Genomics in Rare Disease and Cancer (10 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions