Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that β-catenin pathway activity and adult ...epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that β-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream β-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients.
Background
Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) that have an unknown impact on health but can be clarified through ...reclassification. There is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, and racial/ethnic differences.
Methods
This was a retrospective analysis of persons with and without a personal history of cancer carrying VUS (with or without an accompanying pathogenic or likely pathogenic P/LP variant) in breast, ovarian, and colorectal cancer predisposition genes seen at four cancer care settings (in Texas, Florida, Ohio, and New Jersey) between 2013 and 2019.
Results
In 2715 individuals included in the study, 3261 VUS and 313 P/LP variants were reported; 8.1% of all individuals with VUS experienced reclassifications and rates varied significantly among cancer care settings from 4.81% to 20.19% (overall p < 0.001). Compared to their prevalence in the overall sample, reclassification rates for Black individuals were higher (13.6% vs. 19.0%), whereas the rates for Asian individuals were lower (6.3% vs. 3.5%) and rates for White and Hispanic individuals were proportional. Two‐year prevalence of VUS reclassification remained steady between 2014 and 2019. Overall, 11.3% of all reclassified VUS resulted in clinically actionable findings and 4.6% subsequently changed individuals' clinical managements.
Conclusions
The findings from this large multisite study suggest that VUS reclassification alters clinical management, has implications for precision cancer prevention, and highlights the need for implementing practices and solutions for efficiently returning reinterpreted genetic test results.
Number of reclassified unique variants of uncertain significance (VUS) by gene as a function of the total number of VUS. The number of unique VUS is shown on the right axis and that number of reclassifications are on the left axis.
The 5, 10 methylenetetrahydrofolate reductase (MTHFR) enzyme is a catalyst in the folate metabolism pathway, the byproducts of which are involved in the remethylation of homocysteine to methionine. ...Methionine is a precursor for a major DNA methyl donor and is important for DNA methylation and gene regulation. Rare mutations in the
MTHFR
gene have been associated with autosomal recessive MTHFR deficiency leading to homocystinuria. In addition, two polymorphic variants in this gene (C677T and A1298C) have been implicated in a mild form of MTHFR deficiency associated with hyperhomocysteinemia. Mild to moderate hyperhomocysteinemia has been previously implicated as a risk factor for cardiovascular disease. Further, the presence of these variants, with and without mildly elevated levels of homocysteine, has been studied in relation to several multifactorial disorders including recurrent pregnancy loss, neural tube defects and congenital anomalies, cancer, and neurodevelopmental disorders. Given this wide spectrum of purported clinical implications and the prevalence of these polymorphisms, genetic counselors may encounter questions regarding the significance of
MTHFR
polymorphisms in a variety of settings. Here we present a brief background of the
MTHFR
polymorphisms, review of the literature regarding clinical considerations, and discussion of relevant genetic counseling aspects through case vignettes. Educational resources for patients and providers are also included.
Ovarian endometrioid adenocarcinoma with yolk sac component has been reported in fewer than twenty cases in the literature. A majority of the diagnoses are described in postmenopausal women without ...specific reference to germline genetic testing. We describe, to our knowledge, the first case in the English literature of a premenopausal woman that presented with an ovarian endometrioid adenocarcinoma with focal yolk sac component and was subsequently found to have a germline MSH2 mutation confirming a diagnosis of Lynch syndrome. Concurrent diagnosis of ovarian endometrioid adenocarcinoma with yolk sac tumor and Lynch syndrome is an extremely rare finding in a young patient and requires careful follow-up. Genetics evaluation and testing may be reasonable for individuals with this rare or mixed tumor pathology at young age of onset and can have clinical utility in guiding future cancer treatment or surveillance.
•Ovarian endometrioid adenocarcinoma with associated yolk sac tumor is a rare entity.•A thorough histological and immunohistochemical assessment is required to reach an accurate diagnosis.•Genetics evaluation for Lynch syndrome may be reasonable for rare ovarian tumors.
Background
Use of surveillance mammography and magnetic resonance imaging (MRI) has been understudied among women with variant of uncertain significance (VUS) compared to pathogenic and likely ...pathogenic variants (P/LP).
Methods
Using data from two cancer settings, we calculated use of risk‐reducing mastectomy (RRM) and surveillance during each 13‐month span after genetic testing up to 6 years afterwards for a cohort of genetically elevated risk women.
Results
Of 889 women, VUS carriers were less likely to undergo RRM compared to those with P/LP (hazard ratio HR, 0.17; p = <.001) and high‐risk women were more likely to undergo RRM than average‐risk women (HR, 3.91; p = .005). Longitudinally, surveillance use among unaffected women decreased from 49.8% in the first year to 31.2% in the sixth year after genetic testing. In comparison, a greater proportion of women with a personal history of breast cancer underwent surveillance, which increased from 59.3% in the first year to 63.6% in the sixth year after genetic testing. Mammography rates did not differ between women with P/LP and VUS within the first 13 months after genetic testing and up to 4 years afterward. Over the first 4 years after genetic testing, women with VUS were less likely to undergo annual MRIs compared to P/LP.
Conclusion
The authors found that VUS, whether in high or moderate penetrance breast cancer susceptibility genes, was associated with lower use of annual breast MRI compared to P/LP variants and equivalent use of annual mammography. These results add important evidence regarding VUS‐related breast surveillance.
This study compares the use of breast surveillance between women with variants of uncertain significance (VUS) and pathogenic variants in breast cancer susceptibility genes. The authors find that VUS carriers, both with and without a personal history of cancer, have significantly lower use of annual breast MRI compared to those with pathogenic or likely pathogenic variants, which adds important evidence regarding VUS‐related surveillance.
Background
Uptake of cancer risk management based on inherited predispositions, which encompasses bilateral mastectomy (BLM), bilateral salpingo‐oophorectomy (BSO), and intensified screening, is the ...primary motivation for cascade testing for hereditary breast and ovarian cancer (HBOC). However, long‐term outcome data for cascade testers are lacking.
Methods
Medical records were ed for all unaffected women with pathogenic variants in HBOC genes from 2 cancer hospitals (2013‐2019) with at least 1 year of follow‐up to compare the uptake of surgery and screening between cascade and noncascade testers.
Results
Cascade testers (79.8%) were younger than noncascade testers (mean age, 37.6 vs 43.5 years; P = .002). Among women aged ≥40 years, 43% underwent BLM, and 71.6% underwent BSO, with no significant difference in uptake between cascade and noncascade testers. The mean time to BSO among cascade testers was shorter among women aged ≥40 years versus those aged <40 years (11.8 vs 31.9 months; P = .04); no such difference was observed among noncascade testers. Mammography and breast magnetic resonance imaging rates were low in the recorded 6 years for both groups after genetic counseling.
Conclusions
Management uptake among cascade testers is high with rates comparable to those for unaffected BRCA‐positive women. A large proportion of women act on cascade test results, and this represents a novel report of utilization of cancer management strategies.
This study compares the long‐term uptake of cancer risk reduction strategies between cascade and noncascade genetic testers. The authors identify high uptake of cancer risk reduction strategies among cascade testers with rates comparable to those of unaffected BRCA‐positive women. This represents a novel report of health care utilization in this population.
Germline mutations in
cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare
tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family ...with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of
. The majority of families were of Ashkenazi Jewish descent, and the
c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with
normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including
, and
) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that
c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE:
c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.
A quality improvement initiative (QII) was conducted with five community-based health systems' oncology care centers (sites A–E). The QII aimed to increase referrals, genetic counseling (GC), and ...germline genetic testing (GT) for patients with ovarian cancer (OC) and triple-negative breast cancer (TNBC).
QII activities occurred at sites over several years, all concluding by December 2020. Medical records of patients with OC and TNBC were reviewed, and rates of referral, GC, and GT of patients diagnosed during the 2 years before the QII were compared to those diagnosed during the QII. Outcomes were analyzed using descriptive statistics, two-sample t-test, chi-squared/Fisher's exact test, and logistic regression.
For patients with OC, improvement was observed in the rate of referral (from 70% to 79%), GC (from 44% to 61%), GT (from 54% to 62%) and decreased time from diagnosis to GC and GT. For patients with TNBC, increased rates of referral (from 90% to 92%), GC (from 68% to 72%) and GT (81% to 86%) were observed. Effective interventions streamlined GC scheduling and standardized referral processes.
A multi-year QII increased patient referral and uptake of recommended genetics services across five unique community-based oncology care settings.
•A coordinated quality improvement initiative was completed in five community-based health system oncology care centers.•Referral, genetic counseling, and genetic testing improved for patients with ovarian and triple-negative breast cancer.•Average time to completion of genetic testing for patients with ovarian cancer significantly decreased at almost all sites.•The most effective quality improvement interventions standardized genetic counseling referral and delivery processes.
Program evaluation can identify the successes and challenges of implementing clinical programs, which can inform future dissemination efforts. A cancer genetics improvement program, disseminated from ...the Lead Team's institution to five health systems (Participating Sites), was genetic counselor led, using virtual implementation facilitation to support Participating Sites' performance of quality improvement (QI) activities over several years. Program implementation and outcome evaluations were performed and included evaluation of program delivery and initial effects of the program on Participating Sites. A logic model guided evaluation of program implementation (inputs, activities, outputs, delivery/fidelity, and coverage/reach) and initial outcomes (short‐term and intermediate outcomes). Data were collected from program documents and an Evaluation Survey of Participating Site team members (21 respondents), compared against the Lead Team's expectations of participation, and analyzed using descriptive statistics. All program inputs, outputs, and activities were available and delivered as expected across the five Participating Sites. The most frequently used activities and inputs were facilitation‐associated meetings and meeting resources, which were rated as useful/helpful by the majority of respondents. Nearly all respondents noted improvement in short‐term outcomes following participation: 82.4% reported increased awareness of clinical processes, 94.1% increased knowledge of QI methods, 100% reported increased perceived importance of QI, 94.1% increased perceived feasibility of QI, and 76.5% reported increased problem‐solving skills and self‐efficacy to use QI at their site. Intermediate outcomes (identifying barriers, developing interventions, improved teamwork, and capacity) were achieved following program participation as indicated by the results of the program document review and Evaluation Survey responses. Implementation challenges at Participating Sites included staffing constraints, difficulties obtaining buy‐in and participation, and developing interventions over time. The multi‐site improvement program was delivered and implemented with high levels of fidelity and resulted in improved short and intermediate outcomes. Future research will evaluate long‐term, patient‐level outcomes associated with site‐specific QI interventions.
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