Alternatively, the family could have a mutation in a yet-unidentified gene that causes LS or a predisposition to colon cancer. Another explanation for a negative mutation test is that, by chance, the individual tested in the family has developed colon cancer through a nongenetic mechanism (i.e., it is a sporadic case), while the other cases in the family are really due to a germline mutation. If this scenario is suspected, testing another affected individual is recommended. Finally, failure to detect a mutation could mean that the family truly is not at genetic risk despite a clinical presentation that suggests a genetic basis. If no mutation can be identified in an affected family member, testing should not be offered to at-risk members. They would remain at increased risk of CRC by virtue of their family history and should continue with recommended intensive screening. (Refer to the Interventions/LS section of this summary for more information.)
There is overlap in the phenotype of families with LS and AFAP, as both syndromes can present with multiple colonic adenomas and extracolonic cancers. (Refer to the Attenuated FAP section of this summary for more information.) A clinical finding that would suggest AFAP over LS is fundic gland polyposis of the stomach. The presence of uterine, gastric, urinary, and/or ovarian cancers within a family would favor the diagnosis of LS. Genetic counseling for the affected individual is suggested to determine the best options for genetic testing.
An interest in noninvasive methods of screening has led to evaluation of new screening techniques, including CT colography (also known as virtual colonoscopy or CT colonography) and detection of DNA mutations in stool. One study of 78 individuals with LS, all of whom underwent CT colography and colonoscopy, showed that CT colography had good sensitivity for large polyps but poor sensitivity for small polyps. Therefore, CT colography was not recommended as a primary tool for LS surveillance. These findings are of particular importance in LS screening, since neoplasms in this setting begin as subtle flat lesions. The stool DNA mutation tests detect somatic mutations derived from the tumor tissue and cannot replace germline mutation testing. This method has not been adequately evaluated in high risk populations such as patients with FAP or LS. (Refer to the PDQ summary on Colorectal Cancer Screening for more information on these methods.)
Diagnostic strategies for all individuals diagnosed with CRC
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?[282,283] 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. The Working Group reported that there is 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:[282,283]
- 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.