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Tag Archives: apc gene
Adenoma Carcinoma Sequence
Adenoma Carcinoma Sequence
Steps and pathway to cancer development:
1. “First hit”: germline or somatic mutations to:
- APC, mismatch repair genes (MSH2)
2. “Second hit”: methylation, inactivation of normal alleles:
- APC, B-catenin, MSH2
Adenomas
3. Protooncogene mutation: k-ras
4. Homozygous loss of other tumour suppressor protein: p53
5. Carcinoma: many genes involved and altered
Posted in Colon
Tagged adenoma, Adenoma Carcinoma Sequence, apc, apc gene, b-catenin, Beta catenin, Cancer pathway, Colon, colon cancer, Colorectal carcinoma, Colorectal carcinoma pathway, DNA methylation, k-ras, methylation, mismatch repair genes, MSH2, p53
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Attenuated Familial Adenomatous Polyposis
Attenuated Familial Adenomatous Polyposis
AFAP (Attenuated)
Genetics:
- mutations in APC gene 5q chromosome, exon 9 (5’, 3’ ends)
- also mutations to MYH (base excision repair gene)
Gross: flat, plaque-like, less than 100, right colon
Histology
- adenomas, may have adenomatous flat epithelium
Clinical: adenocarcinoma later ~55yrs
Posted in Colon
Tagged adenoma, AFAP, apc gene, Attenuated familial adenomatous polyposis, Colon adenoma, colon adenomas, Colon poylps, colorectal polyps, Familial Adenomatous Polyposis, Familial adenomatous polyposis coli, Many colon polyps, myh gene
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Familial Adenomatous Polyposis
Familial Adenomatous Polyposis
Classic Familial Adenomatous Polyposis
Genetics: Autosomal dominant
- mutations in APC gene 5q chromosome
- APC is a tumour suppressor gene
- non-fnxl APC pr- cannot bind B-catenin
- B-catenin binds to Tcf-Lef proteins
- this activates genes involved in proliferation and inhibition of apoptosis
Extracolonic lesions:
- Fundic gland polyps
- Gardner’s syndrome and extra gastrointestinal lesions (desmoid tumors, epidermoid cyst, osteoma)
- Turcot’s syndrome and medulloblastoma
Diagnosis criteria:
a) 100 plus colorectal polyps
b) germ line mutation in APC gene
c) family history of APC
d) at least one of epidermoid cyst, osteoma or desmoid tumor
Gross: sm, lg adenomas, polyps in colon, distally in colon
Histology: adenomas, may have adenomatous flat epithelium
Clinical: – risk of adenocarcinoma is ~100% by age 50
Posted in Colon
Tagged apc, apc gene, Classic Familial Adenomatous Polyposis, Classic Familial Adenomatous Polyposis Coli, colorectal polyps, Desmoid tumor, epidermoid cyst, Familial Adenomatous Polyposis, Familial adenomatous polyposis coli, family history of APC, FAP, germ line mutation in APC gene, Osteoma
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Fundic Gland Polyp
Fundic Gland Polyp
Gross appearance and location:
- multiple sessile polyps
- fundus or body of stomach
Histology:
- mixture of mucous and specialized glands
- associated with familial adenomatous polyposis syndrome (FAP) if numerous
Genetics:
sporadic: β-catenin mutations
FAP: APC mutations
Posted in Stomach
Tagged apc gene, APC mutation, Familial Adenomatous Polyposis, familial adenomatous polyposis syndrome, Fundic Gland Polyp, Fundic Gland Polyps, Fundic polyp, Gastric polyp, Stomach polyp, Stomach polyps, β-catenin, β-catenin mutation
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Turcot syndrome
Turcot syndrome
Tumors of the CNS
Two-thirds with APC gene mutations develop medulloblastomas
One-third with HNPCC gene mutations develop glioblastomas
Posted in Syndrome
Tagged , apc gene, Glioblastoma, HNPCC gene, medulloblastoma, turcot syndrome
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Familial Adenomatous Polyposis Syndrome
Familial Adenomatous Polyposis (FAP) Syndrome
Familial Adenomatous Polyposis Syndrome Inheritance pattern
- autosomal dominant inheritance
- APC gene is on chromosome 5q21
- APC gene plays a role in the WNT pathway in the degradation of the beta-catenin
- beta-catenin role is to turn on transcription factors in the nucleus that lead to cell cycle progression
-mutations in the APC leads to absence of b-catenin degradation and signal independent tranlocation into the nucleus where it turns on the cell cycl
Familial Adenomatous Polyposis Syndrome Clinical Presentation
- two types of clinical presentations:
Classic Familial Adenomatous Polyposis
- minimum of 100 colonic polyps
- polyps in ampulla of Vater – this leads to a prophylactic colectomy in siblings and first-degree relatives which are at risk
Attenuated Familial Adenomatous Polyposis
- patients tend to develop fewer polyps (average 30), and most of the polyps are located in the proximal colon
- lifetime risk of cancer development is usually around 50%
Gardner syndrome
- polyps identical to those in classic FAP
- multiple osteomas (particularly of the mandible, skull, and long bones)
- epidermal cysts
- fibromatosis – desmoid tumors
- less frequent are abnormalities of dentition, such as unerupted and supernumerary teeth
- higher frequency of duodenal and thyroid cancer
Turcot syndrome
- combination of adenomatous colonic polyposis and tumors of the CNS
2/3 have have APC gene mutations and develop brain medulloblastomas
- 1/3 have mutations in one of the genes associated with HNPCC and develop brain glioblastomas
Gross Features of Familial Adenomatous Polyposis
-hundreds to thousands of adenomas evenly distributed through colorectum and appendix
- adenomas range from microscopic to 1cm in diameter with larger adenomas found in the rectosigmoid
- rectum occasionally spared, especially in the attenuated FAP
- colorectal carcinomas may be multifocal
Microscopic Features of Familial Adenomatous Polyposis
- histologically identical to sporadic adenomas
- normal intervening mucosa
- adenomas evolve from single adenomatous crypts
Symptoms and Management
- patients may be asymptomatic before puberty
- initial symptoms are rectal bleeding and diarrhea
- carcinomas start about 6 years after first symptoms
- 100% colon cancer without intervention
- treatment is prophylactic total colectomy
- following colectomy, the most common cause of death is periampullary cancer in 20%
Posted in Colon, GI, Syndrome
Tagged , adenoma, apc, apc gene, b-catenin, Cancer, carcinoma, Colon, colorectal, Familial Adenomatous Polyposis, gardner, periampullary cancer, polyps, Syndrome, turcot
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