As introduced earlier, although some sporadic cancers will be truly sporadic and due entirely to somatic mutation(s), other cancers that may appear to be sporadic likely reflect a predisposition to specific cancer(s) due to familial variants in one or more genes. This raises the possibility of using genetic testing to screen for germline pathogenic variants that might inform risk estimates for members of the general population or for families with insufficient family history to implicate a hereditary cancer syndrome. Here we illustrate the issues involved in the case of two common neoplasias: breast cancer and colorectal cancer.
BRCA1 and BRCA2 Testing
Identification of a germline pathogenic variant in BRCA1 or BRCA2 in a patient with breast cancer is of obvious importance for genetic counseling and cancer risk management for the patient’s children, siblings, and other relatives, who may or may not be at increased risk. Such testing is of course also important for the patient’s own management. For instance, in addition to removal of the cancer, a woman found to carry a BRCA1 pathogenic variant might also choose to have a prophylactic mastectomy of the unaffected breast or a bilateral oophorectomy simultaneously to reduce cancer risk while minimizing the number of separate surgeries and anesthesia exposures. Finding a pathogenic variant in the proband or a first- degree relative would also allow targeted testing in the rest of the family.
Importantly, however, the fraction of all female breast cancer patients whose disease is caused by a germline pathogenic variant in either the BRCA1 or BRCA2 gene is small, with estimates that vary between 1% and 3% in populations unselected for family history of breast or ovarian cancer, or for age at onset of the disease. Male breast cancer is 100 times less common than female breast cancer, but when it occurs, the frequency of germ line pathogenic variants in hereditary breast cancer genes, particularly BRCA2, is ~16%.
Until quite recently, the cost of analysis of BRCA1 and BRCA2 was used to justify limiting testing to those patients most likely to be carrying a pathogenic variant, such as all male breast cancer patients and all women younger than 50 years with breast cancer, women with bilateral breast cancer, or women with first- and second- degree relatives with ovarian cancer or breast cancer. However, as the cost of sequencing falls, and large panels of breast cancer susceptibility genes, including BRCA1 and BRCA2, can now be analyzed for less than it cost previously to sequence just BRCA1 and BRCA2, testing guidelines are inevitably undergoing ongoing reevaluation. Testing at least BRCA1 and BRCA2 in all women with high-risk, early-stage, human epidermal growth factor receptor 2 (HER2)– negative breast cancer has gained further support as treatment with PARP inhibitors has been shown to increase survival in individuals with germline BRCA1/ 2 pathogenic variants.
Colorectal Cancer Germline Testing
LS is an autosomal dominant cancer predisposition syn drome with up to an 80% lifetime risk of cancer of multiple types. LS patients harbor germline pathogenic variants in the MMR genes (MLH1, MSH2, MSH6, PMS2, and EPCAM promoter deletion). Only 4% of patients with colon cancer, not selected for a family history of cancer, carry a germline pathogenic variant in one of these genes; an even smaller fraction carry pathogenic variants in APC, causing FAP. As with breast cancer, geneticists need to balance the cost and yield of sequencing hereditary colorectal cancer genes in every patient with colon cancer against the obvious importance of finding such a pathogenic variant for the patient and their family. Also of clinical benefit in identifying individuals with LS is the rationale for immunotherapy when tumors exhibit a characteristic high mutational burden.
For LS, clinical factors such as multiple polyps, early age at onset (age <50 years), the location of the tumor in more proximal portions of the colon, multiple synchro nous or metachronous colorectal cancers, a family history of colorectal or other cancers (particularly endometrial cancer), and cancer in relatives younger than 50 years of age, all boost the probability that a patient with colon cancer is carrying a pathogenic variant in an MMR gene. Molecular studies of the tumor tissue to look for evidence of the MSI+ phenotype (as discussed earlier in this chapter) or absence of MSH2 and/ or MSH6 protein by antibody staining in the tumor also increase the probability that an individual with colorectal cancer carries a germ line pathogenic variant in an MMR gene. Unfortunately, loss of MLH1 protein staining in tumors due to promoter methylation is a frequent epigenetic finding in sporadic colon cancers and is therefore much less predictive of LS.
Combining clinical and molecular criteria allows the identification of a subset of colorectal cancer patients in whom the probability of finding a germline pathogenic variant in an MMR gene is much greater than 4%. These patients are clearly the most cost- effective group in which sequencing could be recommended. However, as with all such attempts at cost effectiveness, limiting the number of patients studied to increase the yield of patients with positive results inevitably results in missing a sizable minority (20%) of patients with LS. Again, the cost of testing must be reevaluated as technology gets less expensive and the therapeutic importance of identifying cancer predisposition is becoming clearer. More detailed discussions of genetic testing will be presented in Chapter 19.
For FAP, the presence of hundreds of adenomatous polyps at an early age, multiple sebaceous adenomas, or the extracolonic manifestations of Gardner syndrome are sufficient to trigger germline testing for an APC pathogenic variant. There are, however, certain APC pathogenic variants that result in many fewer polyps and no extracolonic features (referred to as attenuated FAP). Attenuated FAP can be confused clinically with LS, but the tumors generally lack MMR defects or microsatellite instability.
