Lynch Syndrome and Breast Cancer Risk: Weighing the Data

Abstract

As we continue to expand our understanding of the genotype-phenotype correlations in Lynch syndrome (LS), we must be cautious in the design of studies and interpretation of findings to responsibly serve our patients with LS with as accurate information as possible. Although pathogenic variants (PVs) in the mis-match repair (MMR) genes MLH1, MSH2/EPCAM, MSH6, and PMS2 are all associated with LS, each gene is associated with a unique risk profile. MLH1 and MSH2 have been associated with the highest risk for LS-associated cancers, whereas risk for colorectal cancer is significantly lower for MSH6 and PMS2 PV carriers. 1 In studies of high-risk colorectal cancer cohorts, MSH6 and PMS2 PVs are less commonly identified than MLH1 and MSH2, but use of clinical multigene panel testing is expanding the identification of carriers of PVs in these genes, often in individuals and families lacking the classic pattern of cancers associated with LS. 2,3 The large data sets being generated by genetic testing laboratories can be assets for research and can allow for gene-specific risk analysis. However, analytical caution needs to be taken to account for the biases that arise from patient selection for clinical genetic testing, and family history and clinical data provided to commercial laboratories may be incorrect or inaccurate. In the article accompanying this editorial, Stoll et al 2 add data from a large cohort of MMR carriers and demonstrate a successful strategy for using commercial laboratory data to assess associations between PVs and cancer risk. Their cohort included 441,996 women undergoing multigene panel testing, 3,362 (0.08%) of whom were found to have a PV in an MMR gene (MLH1, n = 462; MSH2, n = 653; MSH6, n = 985; and PMS2, n = 1,262). In their analysis, a standardized incidence ratio was calculated by comparing the incidence of breast cancer in carriers of PVs in MMR genes to that in the US SEER Program registry. However , to account for the study population having a more significant cancer history than the general population, PV carriers were also compared with other subpopu-lations within the laboratory cohort, including women who were negative for a PV in any cancer predisposition gene when testing was performed for evaluation for hereditary breast or ovarian cancer (HBOC) and/or LS, evaluation for HBOC only, and evaluation for LS only. No excess in breast cancer risk was noted when compared with SEER or any laboratory comparison group for any of the MMR genes. In the cohort in the study by Stoll et al, 2 PVs in MSH6 and PMS2 were more common in women undergoing genetic testing for the indication of HBOC than in women being tested as a result of suspicion of LS. Other studies of clinical testing populations have also found a predominance of MSH6 and PMS2 PVs in individuals meeting HBOC guidelines rather than LS. 4 However, this pattern does not confirm that these genetic variants increased the risk for breast cancer. This distribution of PVs in laboratory cohorts likely reflects that, other than MSH6-associated endome-trial cancer risk, PVs in MSH6 and PMS2 confer only a modest risk for colorectal and other LS-associated cancers. Carriers of PVs in these genes are less likely to meet criteria for LS, which were developed to initially identify those families with higher penetrance PVs. Stoll et al 2 have provided a systematic examination of a large laboratory cohort using the proper comparison groups to put the frequency of MSH6 and PMS2 PVs by testing criteria into context and have provided strong evidence against the association of breast cancer with any of the MMR genes. Before widespread panel testing, most analyses of breast cancer risk and LS had come from small studies. 5 Data from studies with larger samples are now becoming available. The findings from several studies have concurred with the findings of Stoll et al 2 and have not demonstrated an association between MMR genes and breast cancer risk. 6-8 Other studies have reported moderate increased risks for certain MMR genes. LaDuca et al compared the frequency of PVs in a laboratory cohort of patients diagnosed with cancer to the frequency of the PVs in the Genome Aggregation Database and found that MSH6 was associated with an odds ratio of 1.65 (95% CI, 1.06 to 2.52) for breast cancer. This outcome is below the level of risk that usually is required to change surveillance recommendations. Therkildsen et al 9 reported an increased risk for breast cancer in women between 50 and 69 years of age (incidence rate ratio, 1.9; 95% CI, 1.1 to 3.0), but this analysis was not specific for MMR genes. An outlying analysis raised significant concerns by reporting much higher breast cancer risks, with estimates of 31% and 37% to age 60 for MSH6 and