Colorectal Cancer _ ___________________________________________________________________________
The absolute risk of colorectal cancer by 79 years of age is [90; 91]: • 4% with no family history • 9% with colorectal cancer in one first-degree relative • 16% with colorectal cancer in two or more first-degree relatives • 15% with colorectal cancer in one first-degree relative diagnosed before 45 years of age • 8% with colorectal adenoma in one first-degree relative Family history of two or more relatives with colorectal cancer substantially increases the possibility of a genetic syndrome, and relative to older individuals, young patients reporting a positive colorectal cancer family history are more likely to represent a high-risk pedigree [92; 93]. Patient risk level is categorized as high, increased (moderate), or average based on the presence of specific factors ( Table 2 ) [94]. Familial and Genetic Colorectal Cancer Syndromes Heritable gene mutations that confer elevated risk of colorectal cancer broadly cluster into two groups: stability genes, including mutations in DNA mismatch repair (MMR) genes responsible for Lynch syndrome, and tumor suppressor genes, including APC gene mutations responsible for FAP. Lynch syndrome and FAP account for the vast majority of heritable colorectal cancer cases and 5% to 6% of all colorectal cancer cases [95]. The absolute risks for colorectal cancer in mutation carriers of hereditary colorectal cancer syndromes are [95]: • Lynch syndrome: 50% to 75% by 75 years of age • FAP: Nearly 100% by 45 years of age • Attenuated FAP: 70% lifetime • MYH-associated polyposis: 80% to 100% by 65 years of age
• Peutz-Jeghers syndrome: 39% by 70 years of age • Juvenile polyposis syndrome: 10% to 38% by 60 years of age Individuals with single-gene disorders are at increased risk of developing colorectal cancer, and single-gene disorders related to known syndromes account for 10% to 15% of colorectal cancer cases. The hereditary syndromes and involved genes include Lynch syndrome, FAP, familial colorectal cancer, and rare genetic syndromes [89]. Lynch Syndrome Lynch syndrome is the most prevalent form of hereditary colorectal cancer, accounting for 3% to 5% of all cases. It primarily involves defects in MMR genes, most commonly MSH2 , MLH1 , PMS1 , PMS2 , or MSH6 . In affected families, 15% to 60% of family members possess MSH2 or MLH1 mutations [90; 95; 96]. Lynch syndrome is an autosomal dominant disorder in which families and patients possess a germline mutation in a DNA MMR gene or loss of expression of the MSH2 gene due to deletion in the EPCAM gene. These genes function to maintain DNA fidelity during replication and are inactivated in Lynch syndrome [97]. Genetic Testing . Genetic risk assessment of Lynch syndrome considers family cancer history and patient age if diagnosed with colorectal cancer or malignancies associated with Lynch syndrome. Mutation in MMR genes can be detected using immunohistochemistry techniques (IHCs) or DNA microsatellite instability (MSI) analysis. Several validated computer models predict MMR gene mutation probability (even when MSI or IHC information is absent) and also incorporate family history of endometrial cancer. Mutation detection rates are higher for patients with more striking family histories or informative tumor testing data [98; 99].
COLORECTAL CANCER RISK LEVELS
Risk Level
Factors
Average
Lack of specific risk factors
Increased (moderate)
Inflammatory bowel disease Previous colonoscopy polyp findings: • Small rectal hyperplastic polyps • 1–2 small tubular adenomas with low-grade dysplasia • 3–10 adenomas • 1 adenoma >1 cm • Any adenoma with villous features or high-grade dysplasia • >10 adenomas on a single examination • Sessile adenomas removed piecemeal Family history: • Colorectal cancer or adenomatous polyps in a first-degree relative • Two second-degree relatives with colorectal cancer
High
Diagnosis of Lynch/HNPCC or FAP Family or medical history highly suggestive of hereditary colorectal cancer syndrome
Source: [94]
Table 2
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MDFL2626
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