Underdiagnosis of Hereditary Colorectal Cancers Among Medicare Patients: Genetic Testing Criteria for Lynch Syndrome Miss the Mark.

PURPOSE: Strict clinical criteria used by Medicare for germline testing for Lynch syndrome (LS) could lead to missed diagnoses of hereditary cancer syndromes given variable individual and family phenotypes. The aim of this study was to compare rates and spectrum of pathogenic or likely pathogenic (P/LP) variants in LS and other hereditary cancer genes on the basis of meeting Medicare LS testing criteria. METHODS: Retrospective review of Medicare beneficiaries who had multigene panel testing with an indication of personal or family history of colorectal cancer (CRC) was performed. Ordering providers determined if Medicare LS criteria were met. The results of genetic testing were compared on the basis of whether or not Medicare testing criteria were met. RESULTS: Among 639 Medicare beneficiaries, 495 (77.5%) met testing criteria. Overall rates of P/LP variant identification were similar between those meeting and not meeting testing criteria (18.4% v 11.8%; P = .06). LS was diagnosed more frequently among those meeting testing criteria (10.1% v 4.9%; P = .05). No statistical differences were found in rates of P/LP variant identification for non-LS CRC genes (5.3% v 5.6%; P = .89) or non-CRC genes (4.2% v 2.1%; P = .23). PMS2, MUTYH, and ATM P/LP variants were found at higher rates among those outside of criteria. CONCLUSION: Among Medicare beneficiaries undergoing genetic testing for suspected LS, rates of P/LP variants in actionable cancer genes were similar regardless of whether testing criteria were met. Current testing criteria fail to identify individuals with P/LP variants in PMS2 and other actionable cancer genes. Relaxing LS testing criteria could improve identification of individuals with hereditary cancer syndromes among Medicare beneficiaries.

Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation.

The complexities of gene expression pose challenges for the clinical interpretation of splicing variants. To better understand splicing variants and their contribution to hereditary disease, we evaluated their prevalence, clinical classifications, and associations with diseases, inheritance, and functional characteristics in a 689,321-person clinical cohort and two large public datasets. In the clinical cohort, splicing variants represented 13% of all variants classified as pathogenic (P), likely pathogenic (LP), or variants of uncertain significance (VUSs). Most splicing variants were outside essential splice sites and were classified as VUSs. Among all individuals tested, 5.4% had a splicing VUS. If RNA analysis were to contribute supporting evidence to variant interpretation, we estimated that splicing VUSs would be reclassified in 1.7% of individuals in our cohort. This would result in a clinically significant result (i.e., P/LP) in 0.1% of individuals overall because most reclassifications would change VUSs to likely benign. In ClinVar, splicing VUSs were 4.8% of reported variants and could benefit from RNA analysis. In the Genome Aggregation Database (gnomAD), splicing variants comprised 9.4% of variants in protein-coding genes; most were rare, precluding unambiguous classification as benign. Splicing variants were depleted in genes associated with dominant inheritance and haploinsufficiency, although some genes had rare variants at essential splice sites or had common splicing variants that were most likely compatible with normal gene function. Overall, we describe the contribution of splicing variants to hereditary disease, the potential utility of RNA analysis for reclassifying splicing VUSs, and how natural variation may confound clinical interpretation of splicing variants.

Impact of race and tumor subtype on second malignancy risk in women with breast cancer.

PURPOSE: Women with breast cancer are at increased risk of second malignancy (SM). However, the impact of race and the hormone receptor (HR) status of the primary breast tumor on risk of SM are not known. The purpose of this study is to analyze the incidence of SM in women with a history of breast cancer according to race and HR status. METHODS: In the surveillance, epidemiology, and end results database, multiple primary standardized incidence ratio sessions were used to compare the incidence of SM in women with a history breast cancer to the cancer incidence in the general population. Analyses of SM by age, race, and hormone-receptor status were performed using the absolute excess risk (AER) and observed/expected (O/E) ratio. RESULTS: Younger black women (under the age of 50) were at greater risk of SM with an AER = 76.03 (O/E = 2.3, 95 % CI = 12.19-2.4) compared to younger white women who had an AER = 38.59 (O/E = 1.55, 95 % CI = 1.53-1.58). Older black women (50 years and older) had at an increased risk of SM with an AER = 42.26 (O/E = 1.3, 95 % CI = 1.26-1.34) compared to older white women who had an AER = 11.56 (O/E = 1.07, 95 % CI = 1.06-1.08). Second breast malignancy is the predominant SM in both black and white women. Women with hormone-receptor (HR)-negative breast cancer had higher risk of SMs with an AER = 43.53 (O/E = 1.41, 95 % CI = 1.38- 0.145-3.31) compared to women with HR-positive disease with an AER = 21.43 (O/E = 1.17, 95 % CI = 1.16-0.1.18). In HR-negative women, younger black women had an AER = 96.46 (O/E = 2.99, 95 % CI = 2.70-3.31), younger white women had an AER = 66 (O/E = 2.25, 95 % CI = 2.13-2.36), older black women had an AER = 58.58 (O/E = 1.45, 95 % CI = 1.34-1.57), and older white women had an AER = 20.88 (O/E = 1.14, 95 % CI = 1.11-1.18). CONCLUSIONS: Black breast cancer survivors and women with HR-negative breast cancer are at increased risk of SM, which deserves further evaluation to understand the biological and clinical basis for this increased risk.

Characterization of Courtesy Stigma Perceived by Parents of Overweight Children with Bardet-Biedl Syndrome.

BACKGROUND: A child's obesity is generally perceived by the public to be under the control of the child's parents. While the health consequences of childhood obesity are well understood, less is known about psychological and social effects of having an obese child on parents. We set out to characterize stigma and courtesy stigma experiences surrounding obesity among children with Bardet-Biedl syndrome (BBS), a multisystem genetic disorder, and their parents. METHODS: Twenty-eight parents of children with BBS participated in semi-structured interviews informed by social stigmatization theory, which describes courtesy stigma as parental perception of stigmatization by association with a stigmatized child. Parents were asked to describe such experiences. RESULTS: Parents of children with BBS reported the child's obesity as the most frequent target of stigmatization. They perceived health care providers as the predominant source of courtesy stigma, describing interactions that resulted in feeling devalued and judged as incompetent parents. CONCLUSIONS: Parents of children with BBS feel blamed by others for their child's obesity and described experiences that suggest health care providers may contribute to courtesy stigma and thus impede effective communication about managing obesity. Health care providers may reinforce parental feelings of guilt and responsibility by repeating information parents may have previously heard and ignoring extremely challenging barriers to weight management, such as a genetic predisposition to obesity. Strategies to understand and incorporate parents' perceptions and causal attributions of their children's weight may improve communication about weight control.