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

Familial Colorectal Cancer Flashcards

1
Q

What are common symptoms of Lynch syndrome

A

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

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2
Q

What lesion precedes a carcinoma

A

Adenoma

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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

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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

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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

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6
Q

What are the type of genes involved in lynch syndrome

A

Mismatch repair genes

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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

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8
Q

What are the lynch syndrome gene dimer pairs

A

Dimers = MLH1 and PMS2 and MSH2 and MSH6

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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

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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

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11
Q

What are the major lynch syndrome related cancers

A

Major = colorectal, endometrial and ovarian, abdominal

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12
Q

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

A

Amsterdam II Criteria

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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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23
Q

What is a potential targeted therapy for lynch syndrome

A

Pembrolizumab

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24
Q

What is a polyp

A

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

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25
Q

Where are polyps commonly found

A

Commonly found in the colon, stomach, sinuses, bladder, uterus

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26
Q

What are inherited polyposis syndromes

A

Inherited polyposis syndromes are caused by pathogenic genetic variants leading to increased polyp formation

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27
Q

What are the two structures of polyps

A

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

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28
Q

How do you investigate polyps

A

Type, size, amount

Identified with colonoscopy and an indigo dye

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29
Q

What are the classifications of polyps

A

Adenomatous - high risk of becoming cancerous and dysplastic

Hyperplastic-serrated - small, typically benign and not dysplastic

Inflammatory - typically benign

Hamartomatous - inherited polyposis syndromes

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30
Q

What is the difference between hyperplastic-serrated polyps and serrated adenomas

A

Hyperplastic-serrated - small, typically benign and not dysplastic

Serrated adenomas - hyperplastic with dysplasia

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31
Q

What are the types of adenomatous polyps

A

Tubular adenoma, tubulovillous adenoma and villous adenoma

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32
Q

What polyps are hamartomatous

A

Juvenile polyps, Peutz-Jegher Syndrome polyps, and polyps seen in Cowden syndrome

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33
Q

How does size relate to malignancy in regards to polyps

A

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

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34
Q

What is a high risk sign of an inherited polyposis syndrome

A

I a young patient present (<50 years) with lots of polyps this may indicate an inherited polyposis syndrome

35
Q

What genes are involved in inherited polyposis syndromes

A

They are often associated with tumour suppressor genes, such as the APC gene involved with Familial adenomatous polyposis (FAP)

36
Q

How are adenomatous polyps screened

A

Faecal occult blood test - 2-yearly test from 60 years

1-2% abnormal = colonoscopy, of these 10% have colorectal cancer

37
Q

What are the risk factors of adenomatous polyps

A

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
Q

What are the surveillance options for adenomatous polyps

A

Sigmoidoscopy and colonoscopy

39
Q

What is the chemoprevention options for adenomatous polyps

A

Aspirin

40
Q

Are adenomatous polyps benign or malignant

A

Classified as neoplastic polyps - start oof benign but can become malignant

41
Q

How long does it take an adenomatous polyp to progress into cancer

A

5-20 years

42
Q

What are the three histological types of adenomatous polyps

A

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
Q

What is the APC gene

A

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
Q

What are the stages of APC mutation

A

Normal epithelia > APC mutation > dysplastic epithelia > K-ras mutation > ademnoma > p53 mutation > carcinoma > metastatic cancer

Throughout these steps the polyp grows

45
Q

What is Knudson’s two hit hypothesis in relation to APC mutations

A

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
Q

What is the inheritance pattern of FAP

A

It is an autosomal dominant mutation, with De novo mutation rate being 30%

APC gene mutations are 100% penetrant

47
Q

Where are tumours found in FAP

A

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
Q

What is the management of FAP

A

Genetic counselling - predictive genetic APC testing for FDR

Surveillance - colonoscopy.
Endoscopy, MRI

Surgery - elective prophylactic colectomy

49
Q

How does the site of APC mutation influence gene expression/symptoms

A

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
Q

What is attenuated FAP caused by

A

5’, exon 9, 3’ and whole gene deletions in APC gene

51
Q

What is the difference between FAP and attenuated FAP

A

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
Q

What is MUTYH associated polyposis

A

Multiple adenomatous colonic polyps - phenotypically indistinguishable from FAP/AFAP

53
Q

What is the inheritance pattern of MUTYH mutation

A

Autosomal recessive pattern of inheritance

Thus FAP can be differentiated by inheritance

54
Q

How can you identify the difference between multiple adenomatous colonic polyps and FAP

A

Differentiated by inheritance

FAP = AD
MACP = AR
55
Q

What is tested on a polyp gene panel

A 
APC
MUTYH
POLD1 and POLE
AD inheritance
10-100 adenomas
 Some hyperplastic polyps
Too few families to define full phenotype
56
Q

What are sessile serrated polyps

A

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
Q

Are sessile serrated polyps dysplastic

A

Sessile serrated polyps are not usually dysplastic but can undergo dysplasia

58
Q

What are traditional serrated adenomas

A

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
Q

What is the cause of serrated polyposis syndrome

A

While somatic pathway understood a germline cause for serrated polyposis has yet to be found

60
Q

What is the diagnostic criteria for serrated polyposis syndrome

A

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
Q

What is the surveillance options for serrated polyposis syndrome

A

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
Q

What are hamartomatous polyps

A

Tumour-like growths with a mix of tissues - connective tissue, mucus filled glands, retention cysts

63
Q

Are hamartomatous polyps sessile or pedunculated

A

Macroscopically they are usually pedunculated, smooth and vascularised

64
Q

What is the size and histology of hamartomatous polyps

A

Vary in size, and have characteristic histology depending if they are Peutz Jeghers polyps or juvenile

65
Q

Where do hamartomatous polyps usually occur

A

Can occur anywhere in the GI tract - intestinal or extra-intestinal

66
Q

Are hamartomatous polyps neoplastic

A

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
Q

Is family genetic testing required when identifying hamartomatous polyps

A

Family genetic testing may be required
Inherited polyposis syndromes include Peutz Jeghers Syndrome, Juvenile Polyposis Syndrome and PTEN Hamartoma Tumour Syndromes

68
Q

What is Peutz Jeghers Syndrome

A

AD syndrome caused by variants STK11 gene on chromosome 19, p-arm

70-80% = germline variants, 25% De novo

69
Q

What are the clinical features of Peutz Jeghers syndrome

A

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
Q

What are the complications of Peutz Jeghers syndrome

A

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
Q

How is Peutz Jeghers syndrome diagnosed

A

Clinical features

Endoscopy

Histological analysis

STK11 testing confirms diagnosis and aids testing in family members

72
Q

How is Peutz Jeghers syndrome managed

A

GI tract screening - endoscopy, removal of large polyps

Breast screening

Cervical screening

73
Q

What is juvenile polyposis syndrome

A

AD caused by various gene variants involved in TBF BETA signalling pathway

74
Q

What are the genes involved in juvenile polyposis syndrome

A

SMAD4 - chromosome 18, found in up to 50% of patients

BMPR1A - chromosome 10

ENG1 - chromosome 9

75
Q

What are the clinical features of juvenile polyposis syndrome

A

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
Q

How is juvenile polyposis syndromes diagnosed

A

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
Q

How is juvenile polyposis syndromes managed

A

Endoscopy from age 15 or earlier if symptoms present

78
Q

What are PTEN hamartoma tumour syndromes

A

AD caused by PTEN mutations found on chromosome 10, q-arm

79
Q

What is PTEN

A

This is a tumour suppressor gene involved in the mTOR pathway

Ubiquitously expressed protein
PTEN pathogenic variants identified in 85% of PHTS patients

80
Q

What are the PTEN syndromes

A

Cowden syndrome
GI polyps
Risk of malignancy

Banayan-Riley-Ruvalcaba syndrome
Colonic and ileal polyps

Lhermitte-Duclos disease
Cerebella harmatomatous overgrowth

81
Q

What is Cowden syndrome

A

Few to 100 harmatomatous polyps in GI tract in ~95%

Mainly harmatomatous, also ganglioneuromatous, adenomatous or lymphoid

82
Q

What are the features of Cowden syndrome

A

Skin trichilemmomas from adolescence

Thyroid disorders - goitre

Uterine fibroids

Fibrocystic breast

Macrocephaly (84%)

83
Q

What are the complications with Cowden syndrome

A

Increased risk of cancer - thyroid, endometrial, breast

84
Q

How is Cowden syndrome diagnosed

A

Clincial features and genetics

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

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