Maegan Roberts

A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir-Torre variant of Lynch syndrome

Purpose:The Muir–Torre syndrome variant of Lynch syndrome is characterized by the presence of sebaceous neoplasms (adenoma, epithelioma/sebaceoma, carcinoma) and Lynch syndrome–associated cancers (colon, endometrial, and others). Several clinical scoring systems have been developed to identify patients with colon cancer at high risk of Lynch syndrome. However, no such system has been described for patients presenting with sebaceous neoplasms.Methods:Based on logistic regression analysis, a scoring system was developed for patients with sebaceous neoplasm to identify those with the highest likelihood of having Muir–Torre syndrome. The final version of the scoring system included variables such as age at presentation of initial sebaceous neoplasm, total number of sebaceous neoplasms, personal history of a Lynch-related cancer, and family history of Lynch-related cancers.Results:Patients with a score of 3 or more were more likely to have Muir–Torre syndrome (28 of 29 patients), those with a score of 2 had intermediate likelihood (12 of 20 patients), and no patient with a score of 0 or 1 was diagnosed with Muir–Torre syndrome.Conclusion:The Mayo Muir–Torre syndrome risk scoring system appears to identify whether patients who present with sebaceous neoplasms are in need of further Lynch syndrome evaluation using easily ascertained clinical information. Abnormal mismatch repair gene immunohistochemistry of a sebaceous neoplasm is a poor predictor in regard to diagnosing Lynch syndrome.Genet Med 16 9, 711–716.

MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer

PurposeAn association of Lynch syndrome (LS) with breast cancer has been long suspected; however, there have been insufficient data to address this question for each of the LS genes individually.MethodsWe conducted a retrospective review of personal and family history in 423 women with pathogenic or likely pathogenic germ-line variants in MLH1 (N = 65), MSH2 (N = 94), MSH6 (N = 140), or PMS2 (N = 124) identified via clinical multigene hereditary cancer testing. Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in our study population with those in the general population (Surveillance, Epidemiology, and End Results 18 data).ResultsWhen evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% confidence interval (CI), 1.56–2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17–3.92) were associated with a statistically significant risk for breast cancer whereas no association was observed for MLH1 (SIR = 0.87; 95% CI, 0.42–1.83) or MSH2 (SIR = 1.22; 95% CI, 0.72–2.06).ConclusionOur data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants

The variant curation guidelines published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provided the genetics community with a framework to assess variant pathogenicity; however, these rules are not gene specific. Germline pathogenic variants in the CDH1 gene cause hereditary diffuse gastric cancer and lobular breast cancer, a clinically challenging cancer predisposition syndrome that often requires a multidisciplinary team of experts to be properly managed. Given this challenge, the Clinical Genome Resource (ClinGen) Hereditary Cancer Domain prioritized the development of the CDH1 variant curation expert panel (VCEP) to develop and implement rules for CDH1 variant classifications. Here, we describe the CDH1 specifications of the ACMG/AMP guidelines, which were developed and validated after a systematic evaluation of variants obtained from a cohort of clinical laboratory data encompassing ∼827,000 CDH1 sequenced alleles. Comparing previously reported germline variants that were classified using the 2015 ACMG/AMP guidelines to the CDH1 VCEP recommendations resulted in reduced variants of uncertain significance and facilitated resolution of variants with conflicted assertions in ClinVar. The ClinGen CDH1 VCEP recommends the use of these CDH1‐specific guidelines for the assessment and classification of variants identified in this clinically actionable gene.

Assessing, Counseling, and Treating Patients at High Risk for Breast Cancer

Identifying patients at high risk of carrying pathogenic variants in genes is a crucial part of providing both accurate counseling and evidence-based treatment recommendations. Current risk assessment models have strengths and weaknesses that may limit their applicability to specific clinical circumstances. Clinicians must have knowledge regarding variations in available models, how they should be used, and what data they can expect from specific models. In addition, indications for genetic testing are expanding, and the adoption of next-generation sequencing has allowed the creation of multigene testing panels. Complex consequences of panel testing have included an increase in the incidence of identifying variants of uncertain significance and the identification of pathogenic variants in genes for which treatment guidelines are not available. Women diagnosed with breast cancer who carry pathogenic variants in genes with proven associations with breast cancer (BRCA1/2) or highly likely associations (PTEN, PALB2) require additional risk assessment to facilitate treatment decisions that will limit in-breast tumor recurrence and contralateral breast cancer.

Response to ten Broeke et al.

We appreciate the thoughtful feedback by ten Broeke et al. on our manuscript entitled “MSH6 and PMS2 Germ-line Pathogenic Variants Implicated in Lynch Syndrome Are Associated with Breast Cancer.” While we agree with most of the limitations they outline, which had already been included in our discussion, a few points warrant further response. First, we agree with the authors about the advantages of segregation analyses. However, we did not have sufficiently detailed family data to allow us to conduct these analyses. While standardized incidence ratio (SIR) analysis has limitations particularly when the external comparison group may not be comparable to the internal group, we were able to evaluate the specificity of our findings across four cancer types (breast, colon, endometrial, and ovarian), and only breast cancer had findings specific to MSH6 and PMS2. We would also like to emphasize that the magnitude of the SIR we found, using four times the number of cases in the study by ten Broeke, also found a similar SIR estimate for PMS2, namely 2.92 (95% confidence interval [CI]= 2.17–3.92) for our study versus 3.8 (95% CI= 1.9–6.8) for that of ten Broeke. The tighter confidence interval of our estimate is based upon the larger number of breast cancer cases in our study. Although we observed comparable SIRs for PMS2 with ten Broeke as well as comparable aggregate SIRs with that of Engle, the actual SIR estimates depend on the underlying age structure and the weights based on the prevalence of pathogenic variants per gene. The study by Engel included proportionately more individuals with pathogenic variants in MLH1 and MSH2, but the underlying age structure was not described. The study by Engle also did not include PMS2. Our aggregate SIR estimates may be lower because a higher incidence was used to estimate the expected number of breast cancer cases as well as a younger age cohort. Our cumulative risks are much higher, which is in line with what would be expected based on the high proportion of pathogenic variants in MSH6 and PMS2 in our study. Ten Broeke et al. hypothesize that the relatively high frequency of MSH6 and PMS2 pathogenic variants in the general population could have inflated the breast cancer SIRs calculated for these two genes in our study. Our ascertainment method and the frequency of pathogenic variants in these genes may have influenced the calculated SIRs; however, this is unlikely to be the sole explanation for the observed increased risk of breast cancer. The higher frequency ofMSH6 and PMS2 pathogenic variants in the general population compared to MLH1 and MSH2 has been suggested by not only Win et al. but also by Espenchied et al. in addition to our results. By comparing the cancer distribution across our cohort, we were able to compare the magnitude of the SIRs across cancer types, which had similar methods of ascertainment. The cancer distribution is different between genes, with increased breast cancer only associated with MSH6 and PMS2 suggesting that the increased SIRs are not simply due to the frequency of pathogenic variants in MSH6 and PMS2. Furthermore, other groups have also reported an association betweenMSH6 and PMS2 and breast cancer. Espenschied et al. found that the frequency of PMS2 pathogenic variants in breast cancer–only patients was significantly higher than published population frequencies (p= 0.0006), and Couch et al. reported an association with breast cancer for MSH6 using data from the Exome Aggregation Consortium (ExAC) as a reference control (odds ratio [OR]= 1.93; 95% CI, 1.16–3.27, p= 0.01) (ref.). The efforts of the Prospective Lynch Syndrome Database are commendable, but we suspect that the breast cancer cumulative risks available on that website may not be representative of all women with Lynch syndrome. This cohort is also likely subject to ascertainment bias, as study participants are recruited based on patients’ perceived increased colorectal cancer risk and established clinical diagnostic criteria. In addition to our assessment of established Lynch syndrome clinical and testing criteria, Espenschied et al. also found that MSH6 and PMS2 pathogenic variant carriers are more likely to present with a hereditary breast and ovarian cancer phenotype, which may explain why pathogenic variants in these two genes have been historically underreported in the literature. While prospective studies are needed, new cancer associations are not likely to be delineated as long as clinical and research testing for Lynch syndrome continues to be based on previously established criteria (i.e., Amsterdam II criteria and Bethesda Guidelines), which are heavily based on colon cancer diagnoses. Again, as stated in our manuscript, we recognize that this study has inherent limitations and largely agree with the points made by ten Broeke et al. We agree that our results need to be replicated before any standard breast cancer management recommendations are made. Ultimately, studies of population-based cohorts must be performed to minimize the ascertainment biases inherent in all of the studies to date. However, we believe that our data on multigene panel testing adds to the body of knowledge regarding the phenotypic spectrum of Lynch syndrome, which appears to be broader than was previously appreciated.