Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes
Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) continued...
Two single nucleotide polymorphisms (SNPs) identified in genome-wide association studies have been reported to increase CRC risk in MMR gene mutation carriers. (Refer to the Genome-wide searches section of this summary for more information.) Having the C-allele of either SNP increased the risk of CRC in a dose-dependent fashion (with homozygotes at a higher risk than heterozygotes). The first SNP in 8q23.3 increased CRC risk 2.16-fold for homozygote carriers of the SNP. The second SNP, located in 11q23.1, increased CRC risk only in female SNP carriers by 3.08 for homozygotes and 1.49 for heterozygote SNP carriers.
In a study of 684 mutation carriers from 298 Australian and Polish families, nine SNPs within six previous CRC susceptibility loci were genotyped to investigate their potential as modifiers of disease risk in LS. Two SNPs, rs3802842 (11q23.1) and rs16892766 (8q23.3), were associated with CRC susceptibility in MLH1 mutation–positive LS patients. However, a subsequent study of 748 French MMR mutation carriers did not replicate the association between the IGF1 CA repeat and age of CRC onset or the association between SNPs in 8q23.3 and 11q23.1 and CRC risk.
Given the inconsistent results of these studies, genetic testing for these polymorphisms has no clinical utility at present.
Diagnostic strategies for all individuals diagnosed with CRC (universal testing)
The Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a project developed by the Office of Public Health Genomics at the Centers for Disease Control and Prevention, formed a working group to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice. The Working Group was commissioned to address the following question: Do risk assessment and MMR gene mutation testing in individuals with newly diagnosed CRC lead to improved outcomes for the patient or relatives, or are they useful in medical, personal, or public health decision-making?[338,339] The Working Group constructed economic models to assist in analyzing available evidence on clinical utility in estimating how various testing strategies might function in practice. These included mutation frequency, sensitivity and specificity of both IHC and MSI testing, and the cost of these tests. The performance of these tests is based on the risk of positivity of carrying a mutation including family history, age at diagnosis, and extracolonic cancers. In 2009, the Working Group reported that there was sufficient evidence to recommend offering genetic testing for LS to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives. They concluded that there was insufficient evidence to recommend a specific gene-testing strategy among the following four strategies tested:[338,339]
- All individuals with CRC tested for germline mutations in MSH2, MLH1, and MSH6. The average cost per LS detected was estimated to be $111,825.
- All tumors tested for MSI, followed by germline mutation analysis of MSH2, MLH1, and MSH6 offered to those with MSI-H tumors. The average cost per LS detected was estimated to be $47,268.
- All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2, followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. The average cost per LS detected was estimated to be $21,315.
- All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2 followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. If there was absence of MLH1, testing was offered for BRAF mutation–negative tumors. The average cost per LS detected was estimated to be $18,863.