Inheritance:
- Autosomal dominant with very high penetrance FAP, AFAP
- Autosomal recessive (MAP)
- Sporadic
Varients of FAP:
1- classical FAP
2- attenuated FAP
3- MUTYH-associated FAP (MAP)
4- Gardner's syndrome
5- Turcot syndrome
1-Classical Familial adenomatous polypsis FAP:
The most common colorectal polyposis, 1% of all CRC
Prevalence 1 in 14000
The most common colorectal polyposis, 1% of all CRC
Prevalence 1 in 14000
100 - 1000 adenomatous polyps in the colon and rectum.
Average age of onset 15 years
Present with rectal bleeding, anaemia, signand symptoms of maliganacy
Risk of carcinoma if untreated is 100% by middle age
Genetics:
AD
100% penetrence
30% new mutation
AD
100% penetrence
30% new mutation
germ-line mutation of the APC gene on chromosome 5q
APC is a tumour suppressor gene
exact function unknown
-prompt apoptosis in colonic epithelial cells
-role in beta-catenin/Wnt signalling pathways
-role in cell adherence and cytoskeletal organisation
Pathological features:
polyps range from few mms to several cms in size
adenomas are usually tubular, but can be any type
micro-adenomas common.
Associated features:
Duodenal adenomas in 60-90%---->carcinoma(4-12% life time incidence)
fundic glands polyps in 30%
intra-abdominal desmoids
? gastric adenoma ---->carcinoma
extra-intestinal:
sebaceous cysts
osteomas
CHRPE
dental abnormalities
soft tissue tumours
other malignancies:thyroid,panceatic,hepatoblastoma,medulloblastoma.
Diagnosis:
-Identify classical phenotype
-Genetic testing
BSG recommendations: Families with FAP should be refered to the regional clinical genetic service or other specialist service. (grade B)
Flex sigi from age of 14 yearly
Colonoscopy from age of 20 5 yearly
OGD once colorectal adenoma seen from age of 25 3 yearly, then yearly if duodenal polyp found
Large bowel surveillance for FAP family members:
- Mutation carriers : annual flex sigi and alternating colonoscopy to from diagnosis until polyp load indicates need for surgery.
- No mutation : family members at 50% risk shuold have annual surveillance from age 13 to 15 until 30 yrs, and every 3 to 5 yrs therafter until age 60.
- Documented APC gene mutation and signifcant polyp load but wish to defer prophylactic surgery for personal reasons, should be offered 6-mounthly flex sigi and annual colonscopy.
Prophylactic colorectal surgery:
- Patients with typcal FAP should be adviced to undergo prophylactic surgery between the age of 16 and 25 yrs.
- the exact timing of surgery should be guided by polyp numbers, size and dysplasia.
- surgical options include proctocolectomy and ileoanal pouch or colectomy with ileorectaal anastomosis. (grade B)
- because of the substantial risk of upper gastrointestinal malignancy in FAP 3 yearly OGD is recommended from the age of 30 yrs.
Surgical:
- prophylactic colorectal surgery is adviced during the second decade of life.
- the timing and extend of surgery depends on polyp location and burden
- the optimal treatment is panproctocolectomy
- any rectal mucosa that is left behind is at risk of developing carcinoma.
Medical:
Sulindac/ Celecoxib
No protection from development of colorectal cancer
- effect on reducing adenomasmis reversible on its discontiuation
- less succesful for upper GI neoplasia
- do not prevent initial onset of adenomas in children
NSAIDs and cyclooxygenase-2-inhibitors shown to reduce adenoma size and number.
2-Attenuated FAP(AFAP):
fewer polyps
develop at later age (average 35)
predominantly involve proximal colon
3-MUTYH-associated FAP(MAP):
0.4-3 % of all CRC
0.4-3 % of all CRC
Often undistinguishable from other types
10-100 polyps, sometime greater
usually patients > 45 yrs
Often present with colorectal cancer
Upper GI polyps can be seen
Increased risk of breast cancer
Upper GI polyps can be seen
Increased risk of breast cancer
Genetics:
AR
AR
mutation in MUTYH gene in 1p34, base excision repair gene BER
DNA glycosylase involved in DNA oxidase damage repair
The life time risk of homozygous is 100% at 60 yrs
Genetic screening should be offered to partners and first degree relatives of homozygous
Surveillance:
Colonoscopy 2-3 yrly from age of 25
OGD 3-5 yrly from age of 30
Prophylactic surgery should be offered based on the number of polyps and degree of dysplasia.
Breast cancer screening should be considered
The life time risk of homozygous is 100% at 60 yrs
Genetic screening should be offered to partners and first degree relatives of homozygous
Surveillance:
Colonoscopy 2-3 yrly from age of 25
OGD 3-5 yrly from age of 30
Prophylactic surgery should be offered based on the number of polyps and degree of dysplasia.
Breast cancer screening should be considered
4-Gardner's syndrome:
intestinal polyps, oeteomas, dental abnormalities, sebaceous cysts
5-Turcot's syndrome:
intestinal polyps, CNS tumours (usually medulloblastomas)
-Around 25% of all cases are due to new mutation in the APC gene with no family history.
Children of individauls with new mutation are at 50% risk of inheriting the condition.
-all patients need genetic testing and councelling of at risk family members.
-all patients need genetic testing and councelling of at risk family members.
A 20-year-old man was found to have iron deficiency anaemia when he went to donate blood. The Blood Transfusion Service contacted his general practitioner who referred the patient to the outpatient clinic for further investigation.
ReplyDeleteGenerally, the patient was very well. He had a good appetite, his weight was steady and he ate a normal diet. He had a normal bowel habit and had never passed any blood, mucus or diarrhoea in his stools. The patient denied knowledge of any overt blood loss from any other source.
His general practitioner had organised an open access endoscopy which was normal; duodenal biopsies were unremarkable. He had a limited knowledge of his family history as his mother had died in childbirth and as a result he was an only child. His father had died of what he thought was secondary liver and lung cancer but he was unsure.
On general physical examination he was fit and athletic. The skin and mucosal membranes were unremarkable. Pulse was 70 beats per minute and regular with a blood pressure of 132/78 mmHg. Heart sounds were normal and the chest was clear. His abdomen was soft and non-tender with no palpable masses or organs. Rectal examination was normal. On viewing the rectal mucosa through a rigid sigmoidoscope the colonic mucosa was covered in innumerable polyps.
What specific genetic abnormality is responsible for this appearance?
(Please select 1 option)
1-Germline mutation of the STK11 gene on chromosome 19
2-Homozygous mutation of the MYH gene
3-Loss of the APC gene on chromosome 5
4-Mutations in mismatch repair genes (e.g. MSH2)
5-Mutation of the p53 tumour suppressor gene
The patient will need a full colonoscopy and biopsy but the information presented is highly suggestive of familial adenomatous polyposis (FAP), caused by the loss of the APC gene on the short arm of chromosome 5.
Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder caused by a germline mutation of the STK11 (serine threonine kinase 11) gene, usually located on the long arm of chromosome 19. Peutz-Jeghers syndrome is associated with intestinal hamartomatous polyps, but is usually (90%) associated with peri-oral pigmentation.
Hereditary nonpolyposis colon cancer (HNPCC) and MYC polyposis do not cause multiple polyps as suggested in this case. In HNPCC, affected individuals inherit a mutation in one of several genes involved in DNA mismatch repair, including MSH2, MLH1, and PMS2. Homozygous mutations in the MYH gene have been associated with a phenotype of multiple colorectal adenomas with or without cancer. This accounts for a proportion of FAP patients without a pathogenic APC mutation.
Mutations in the p53 tumour suppressor gene are found in many different cancers. While mutations in p53 are seen in cases of colon cancer, the question asks for the specific mutation associated with polyposis coli.
The main differential in this question is between FAP and PJS but the lack of perioral pigmentation favours FAP as the diagnosis.
A middle aged woman presents with recent changes in her bowel habits.
ReplyDeleteShe is investigated as a case of sporadic colonic carcinoma.
What is one mechanism of its tumourigenesis?
(Please select 1 option)
1-Bcl-2 down regulation
2-β-catenin suppression
3-Down regulation of p27
4-K ras suppression
5-p53 up regulation
The cyclin-dependent kinase inhibitor p27 is a negative regulator of the cell cycle and a potential tumour suppressor gene. Its down regulation is associated with occurrence of sporadic colon cancer.
ß-catenin accumulation, not suppression, initiates adenoma formation.
p53 is a tumour suppressor gene.
Activation of K ras oncogene is seen in sporadic colon cancer.
Bcl-2 is an oncogene first described in haemotological malignancies but also implicated in other malignancies such as breast and prostate. Its up regulation makes cells resistant to apoptosis.
Expression may be affected in colon cancer but it is not considered one of the key mutations in the tumourigenesis of sporadic colonic adenocarcinoma.
Which of the following statements regarding colon cancer is correct?
ReplyDelete(Please select 1 option)
1-In familial cases the inheritance pattern is typically autosomal recessive
2-In familial polyposis coli the increased cancer risk is due to inheritance of a mutated tumour suppressor gene
3-In non-familial cases, gene mutations in the cancerous cells are unusual
4-It is a characteristic feature of the Peutz-Jegher syndrome
5-It occurs most commonly in the ascending colon
Both familial polyposis coli and Gardner's syndrome are autosomal dominant.
An allelic deletion of a putative tumour suppressor gene located 5q21-q22, familial adenomatous polyposis (FAP) is an autosomal dominant disorder causing extensive adenomatous polyps of the colon and early onset colorectal cancer.
Quantitative and qualitative alterations in gene expression accumulate in colorectal cancer cells. These include alterations of pro-oncogene expression and chromosomal abnormalities (deletions at 17p and 18q are seen in 70% of colorectal carcinomas).
Peutz-Jegher's syndrome is dominantly inherited pigmentation of skin and mucous membranes and hamartomatous polyps in the stomach and larger intestine. The polyps only rarely undergo malignant change.
The rectum and sigmoid colon are the commonest sites, not the the ascending colon.
Which of the following statements is correct concerning the relationship between type 2 diabetes and colonic cancer?
ReplyDelete1-Increased concentrations of C peptide are a marker of increased colorectal cancer risk
2-Insulin treatment increases recurrence free survival after treatment of colonic cancer
3-The increased risk of colorectal cancer in diabetes is related to BMI
4-The increased risk of colorectal cancer in diabetes is related to total cholesterol
5-Type 1 diabetes has similar risks of colonic cancer as does type 2 diabetes
Type 2 diabetes is associated with a 40-60% increase in the risk of cancer of the large bowel. This increase is linked to changes in HbA1c.
Type 2 diabetes is associated with significantly higher rates of overall mortality and reduced disease free and recurrence free survivals after chemotherapy/radiotherapy and insulin has not been shown to have any effects on mortality.
No association has been found between colonic malignancy and type 1 diabetes, nor gestational diabetes.
A number of studies have independently linked high circulating concentrations of C peptide, as a marker of insulin production, with increased colorectal cancer risk. The molecular basis has not been proven but it may be reasonable to extrapolate it is linked to the growth stimulation effects of insulin.
You receive a letter from a general practitioner (GP) requesting a colonoscopy on a 55-year-old woman,
ReplyDeletewhose sister has been diagnosed with MAP following a
colonoscopy in the Bowel Cancer Screening Programme.
She is otherwise well; her only past medical history is
that of depression and anxiety. Both parents are dead,
but did not have any known colorectal disease.
Which of the following statements is the most accurate?
1-You should organise an urgent colonoscopy for the
patient.
2-There is a 50% chance this patient also has MAP.
3-Presymptomatic genetic testing is indicated for all
first-degree relatives.
4-Presymptomatic testing should be directly requested
by the GP.
5-Her past history of depression is not a risk factor for
psychological distress in presymptomatic testing.
Answer: 3
Once a germline mutation has been identified, presymptomatic testing becomes available for all family
members. The patient does not require any surveillance
procedures until a mutation is identified, unless she has
symptoms that warrant further investigation. MAP is an
autosomal recessive disease, and so she has a 1:4
chance of inheriting the condition (assuming both
parents were carriers); she has a 50% chance of being a
carrier of the mutation. Presymptomatic testing should
be initiated after discussion of all the pros and cons in
individual genetic counselling sessions. In particular,
poor socioeconomic background, elevated pretest
anxiety, lack of information, young age and an individual
tendency towards anxiety and depression are known risk
factors for psychological distress, although do not preclude
presymptomatic genetic testing.
A 32-year-old man with FAP attends for duodenal
ReplyDeletesurveillance. The finding of a 10 mm adenoma using
a forward-viewing gastroscope in the duodenum. The histology report shows a tubulovillous adenoma with low-grade (mild) dysplasia.
What further management should you advise?
1-He should commence on Celecoxib.
2-That he requires a further surveillance upper GI endoscopy
in 3 years.
3-That he requires a further surveillance upper GI endoscopy
in 1–2 years.
4-That he requires urgent referral for a pancreaticoduodenectomy.
5-Removal of this polyp endoscopically is associated
with low complication rates.
Answer 2:
This is Spigelman stage II disease, and he will need
further surveillance in 3 years time. For Spigelman stage
0/I disease, follow-up is at 5 years, and for Spigelman
stage III disease, this interval is reduced to 1–2 years. In
early duodenal disease, the risks of surgery far outweigh
the risk of malignant progression, and this is not severe
enough to warrant major prophylactic surgery. Cox-2 inhibitors
(Celecoxib) are thought to exert an anti-neoplastic
effect by inhibiting the prostaglandin-related cellular
functions such as angiogenesis and cell proliferation. The
use of Celecoxib in duodenal polyposis may be considered
justifiable for Spigelman stages III and IV, even
though the available evidence is conflicting, especially if
patients are young because the endoscopic and surgical
treatment options are associated with significant complications
and recurrence. They should only be considered in
patients with no cardiovascular risk factors until more
data are available. There is an increased risk of haemorrhage
following endoscopic mucosal resection in the
upper GI tract as compared with during colonoscopy.
Therefore, patients with only a few small duodenal
polyps (Spigelman stages I and II) who have a low risk of
developing duodenal cancer may only require follow-up
and not adenoma eradication. Even for those with
Spigelman stage II–III polyposis, the high recurrence rates
when treated endoscopically, which can be up to 100%
in some series, may make it difficult to justify complete
adenoma removal. Patients should be counselled as to
these complication rates if the aim is to try to achieve
local disease control in those with stage II–III disease.
The following is true of the cancer risk in FAP:
ReplyDelete1- Without surgery, the average age of diagnosis is
29 years.
2-The risk of thyroid cancer is in the order of 10% to 15%
3- First-degree relatives of affected patients require a
one–off colonoscopy at age 25 years.
4- It takes on average 15–20 years from the first development
of adenomas to the development of colorectal
malignancy.
5-Patients with a mutation at codon 1309 have a
milder form of FAP and should undergo total colectomy
with IRA.
Answer 4
In FAP left untreated, the average age of CRC development
is 39 years, 15–20 years after the first development
of adenomas. The risk of thyroid cancer in FAP
is 2% to 3%; however, there is no consensus as to
specific surveillance. In first-degree relatives of affected
patients (high-risk members), in families where there
is a known APC mutation, colonoscopic surveillance
should be carried out lifelong because the penetrance
of disease is almost 100%. Where there is no known
APC mutation, high-risk members should have surveillance
continued until age 50 years. Patients who have
mutations at codon 1309 have been described to have
a severe form of FAP, and an IPAA may be advised
due to the risk of developing severe rectal polyposis.