Familial Cancer Syndromes in Colorectal Carcinoma
Joel K. Greenson, MD
TERMINOLOGY
Abbreviations
Familial adenomatous polyposis (FAP)
Adenomatous polyposis gene (APC)
Hereditary nonpolyposis colorectal cancer (HNPCC)
Definitions
Familial cancer syndromes = germline mutations associated with increased incidence of specific cancer types
Many syndromes are related to more than 1 cancer type
Mismatch repair genes = genes that promote genomic stability by initiating DNA repair at time of mitosis
Microsatellites = short DNA repeats in introns that can be detected as stable or unstable as way of predicting mismatch repair of DNA
SYNDROMES
Familial Adenomatous Polyposis (FAP)
Autosomal dominant
Germline mutation in APC
1/3 at codon 1061-1309
Severe polyposis has mutations at codons 1250-1464
Attenuated polyposis has mutations at 5′ and 3′ ends
Desmoid tumors associate with mutations at codons 1403-1578
APC l1307K makes somatic mutations more likely
Incidence: 1 in 5,000
Hundreds of adenomas in childhood or adolescence
Associated with other tumor formation
Gardner syndrome
Osteomas of jaw, epidermoid cysts, thyroid carcinomas, and desmoid tumors
Turcot syndrome
Medulloblastoma
Periampullary carcinoma
Desmoid tumors
Fundic gland polyps (often with dysplasia)
MYH-associated Polyposis
Autosomal recessive
Biallelic inactivation of MUTYH gene
Normally this enzyme repairs oxidative damage to guanine
Failure of enzyme leads to multiple G-C to T-A transversions in DNA
2 common sites of mutation in gene associated with most cases
Immunostain for gene product is now commercially available
Lack of nuclear staining may be a potential screening test; needs to be validated
Incidence: 1 in 5,000
Clinically and pathologically looks identical to attenuated FAP
Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer Syndrome)
Autosomal dominant
Germline mutation in DNA mismatch repair genes (MSH2, MLH1, MSH6, PMS2)
Biallelic mutations lead to multiple cancers at young ages
Detected by sequelae of mismatch repair; instability in short DNA repeats called microsatellites (MS) in introns
2 of 5 MS regions must be unstable for positive diagnosis
Immunohistochemistry for products of MLH1, MSH2, MSH6, and PMS2 can also be performed
Specific gene testing may be indicated if either of these tests is positive
Incidence: 1 in 1,000
2-4% of all colorectal carcinoma
Lifetime risk of colon cancer is up to 80%
Endometrial cancer: 55% lifetime risk
Ovarian cancer: 15% lifetime risk
Small bowel and biliary tract carcinomas
Transitional cell carcinomas of renal pelvis and ureter
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