Indicators of cancer predisposing mutations for colon cancer
- Multiple cases of cancer in a family
- Earlier age of onset
- 2 or more cancers in a single individual
- Presence of non-cancerous extracolonic features, that are a feature of some associated syndrome. Like Congenital Hypertrophy of Retinal Pigment Epithelium (CHRPE) and desmoids may be seen in Familial Adenomatous Polyposis (FAP)
- Presence of uncommon tumors, like Adenoid Cystic Carcinoma (ACC), Sebaceous carcinoma, ampullary and small bowel carcinoma.
- Multiple polyps in colon or rectum.
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Major genetic syndromes in Hereditary Colon Cancer
- Somatic mutations in oncogenes.
- Tumor suppressor genes: Familial Adenomatous Polyposis (FAP) and Peutz Jeghers Syndrome (PJS)
- Mismatch repair genes: Hereditary Non-Polyposis Colon Cancer (HNPCC)
- MYH gene: defective Base Excision Repair
|Tumor Supressor Genes|
|DNA Repair Genes:|
|MLH1, MSH2, MSH6, PMS2||LS|
Absolute risk of colon cancer in mutation carriers
|Syndrome||Absolute risk in mutation carriers|
|FAP||90% by age 45 years|
|AFAP||69% by age 80 years|
|LS||40-80% by age 75 years|
|PJS||39% by age 70 years|
|JPS||17-68% by age 60 years|
Criteria for defining HNPCC or Lynch Syndrome (LS)
Revised Bethesda guidelines
One criterion must be met to consider the tumor for MSI testing.
- Colorectal cancer diagnosed in an individual <50 years of age.
- Presence of synchronous, metachronous colorectal or other LS-associated tumor
- Colorectal cancer with MSI-H pathology in an individual <60y of age (presence of Tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern)
- Colorectal cancer or LS associated tumor diagnosed in at least one first degree relative <50 years of age
- At any age in 2 first degree relatives or second degree relatives.
Difference between MSI high, low and stable
|% of unstable loci|
|MSI-H (High)||>30% of tumor markers are unstable|
|MSI-L (Low)||Atleast 1, but fewer than 30% of markers are unstable|
|MSS (Stable)||No loci are unstable|
Familial Adenomatous Polyposis Syndrome (FAP)
It is an autosomal dominant disorder, characterised by multiple (>100) adenomatous polyps in colon and rectum developing after the first decade of life.
Other features that may be seen are polyps in upper GI tract, CHRPE, Osteomas, epidermoid cysts, supernumerary teeth, desmoid formation, papillary thyroid cancer, small bowel ca, hepatoblastoma, medulloblastoma, etc.
APC gene is a tumor suppressor gene located on chromosome 5q21. Loss of APC is the earliest event in chromosomal instability of colon cancer pathway.
By age of 10 years 15%, by 20 years 75%, and by 30 years 90% of FAP gene carriers have colonic adenomas. Without any intervention, most persons with FAP will develop colon or rectal cancer by fourth decade of life.
Extra-colonic manifestations of FAP syndrome
Duodenal adenomas may be seen in 80-100% of FAP patients, most common site being D1 and D2, ie, first and second part of duodenum, especially in the periampullary region.
UGI endoscopy including side-viewing duodenoscopy should be performed between 25 and 30 years of age in FAP patients to detect duodenal adenomas, followed by subsequent scopy based on Spigelman stage, that takes into account polyp size, polyp number, histology, and dysplasia.
Most common stomach tumors are fundic gland polyps. These are often diffuse and not amenable to endoscopic removal, and are not considered precancerous.
If high-grade dysplasia is seen, polypectomy is done and repeat endoscopic surveillance in 3-6 months. Along with that, daily proton pump inhibitors are usually prescribed.
Next extracolonic tumors are gastric adenomas that may be seen in 2-12% of patients with FAP. They are usually treated with endoscopic polypectomy.
Genetic testing and screening for FAP
Genetic diagnosis of FAP requires <10cc of blood in which lymphocyte DNA is tested for APC mutation, which detects the mutation in approximately 80%.
In individuals with an APC gene mutation positive, screening should be initiated at 10-15 years of age. It should be done annually with flexible sigmoidoscopy or colonoscopy.
At-risk individuals who are mutation-negative should undergo at least one flexible colonoscopy at 18-25 years of age. MYH testing should be considered if APC is negative and history is compatible with recessive inheritance.
Treatment if polyps are detected in an individual
Upon the manifestation of polyposis, colectomy (surgical removal of colon) is the only effective management. The various options available for surgical resection are
- Restorative proctocolectomy with IPAA, after which annual surveillance of the ileal pouch is required as the cumulative risk of developing adenomas in the pouch is 75% at 15 years.
- Subtotal colectomy with Ileo-rectal anastomosis for <1000 colonic adenomas and <20 rectal polyps,
- Total proctocolectomy with ileostomy in low rectal cancer in whom sphincter cannot be spared.
Chemoprevention strategies for FAP syndrome
Celecoxib – Specific COX-2 inhibitor
Sulindac – Non-specific COX-2 inhibitor
Omega-3-PUFA (Eicosapentaenoic acid): reduce rectal poly number and size
Heriditary Non-Polyposis Colon Cancer or Lynch Syndrome
It is characterized by Microsatellite instability or defect in DNA Mismatch repair genes, MSH2, MLH1, MSH6, and PMS2. It accounts for 1-3% of all colorectal cancers, and is an Autosomal Dominant disorder with an early age of onset. Right sided colon tumors are more commonly seen. There may be presence of synchromous and metachronous colorectal neoplasms.
Extracolonic tumors seen in HNPCC
Most common extra-colonic malignancy is endometrial carcinoma, with a risk of occurrence of 71% risk in MSH2 carriers and 44% in MLH1 carriers. It is most commonly seen at lower uterine segment, with common histologies being endometrial, clear cell, uterine papillary serous, and malignant mixed Mullerian tumors.
Surveillance/screening for HNPCC or Lynch Syndrome
Colonoscopy is recommended every 1-2 years starting at ages 20-25 years (age 30 years for those with MSH6 mutations), or 10 years younger than the youngest age of the patient diagnosed in the family.
Also recommended annually:
|Endometrial sampling and TVS of uterus and ovaries||Ages 30-35 y|
|Urinalysis with cytology||Ages 25-35y|
|history, examination, education, genetic counselling regarding Lynch syndrome||Age 21 y|
Role of chemoprevention
CAPP2 trial has shown that 600mg aspirin/day for a mean of 25 months substantially reduced cancer incidence in LS.
Surgical management of HNPCC or Lynch Syndrome
Extended colectomy (total or subtotal) is done as the incidence of metachronous colorectal cancer is 16% at 10 years, 41% at 20 years, and 63% at 30 years after segmental colectomy. It gives a survival advantage of around 4 years, with a 12% risk of developing cancer in the rectal remnant at 12 years post-colectomy.
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