A retrospective cohort study of genetic referral and diagnosis of Birt-Hogg-Dubé Syndrome in patients with Trichodiscoma and Fibrofolliculoma skin lesions.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a genetic condition caused by pathogenic variants in the FLCN gene resulting in benign skin lesions, spontaneous pneumothorax, and increased risk for a variety of renal tumors. Skin manifestations of BHD include trichodiscoma (TD) and fibrofolliculoma (FF), which may represent the same pathologic entity. These lesions can identify BHD patients, who upon positive genetic testing can be considered for life-long surveillance for renal neoplasms. OBJECTIVE: To characterize patients diagnosed with TD and FF including rates and outcomes of genetics referral. METHODS: Retrospective chart reviews of patients with confirmed or possible diagnosis of TD or FF at the University of Michigan from September 2002 through October 2020 to assess pathologic findings, personal and family history of BHD manifestations, referral for genetic evaluation, and genetic testing results. RESULTS: 64 patients had a pathologic diagnosis of TD or FF, 16 of whom (25%) were referred to cancer genetics. Fourteen patients completed genetic evaluation, 9 of whom were diagnosed with BHD (64%), with 6 unique pathogenic variants in FLCN. CONCLUSION: Providers should consider referral for genetic evaluation for patients with biopsy-proven TD or FF, as early diagnosis of BHD provides the opportunity for early detection and treatment of other BHD-associated conditions.

Family Recall of and Response to Germline Pathologic Variants Found on Paired Tumor-Germline Sequencing in Pediatric Oncology.

PURPOSE: Paired tumor-germline sequencing can identify somatic variants for targeted therapy and germline pathogenic variants (GPVs) causative of hereditary cancer/tumor predisposition syndromes. It is unknown how patients/families in pediatric oncology use information about an identified GPV. We assessed recall of germline results and actions taken on the basis of findings. METHODS: We completed phone surveys with patients (and/or their parent) with GPVs identified via a single academic medical center's paired tumor-germline sequencing study. Seven hundred forty pediatric (aged 0-25 years) oncology patients were enrolled in this sequencing study between May 2012 and August 2021. Ninety-six participants (13.0%) had at least one GPV identified and were therefore eligible for this survey. The parent/guardian (for patients younger than 18 years or deceased patients) or patients themselves (if 18 years or older) were contacted. Survey topics included germline result recall, experience with genetic counseling, changes to patient's cancer treatment/screening, sharing of results with family members, and lifestyle changes. RESULTS: Fifty-three surveys (response rate, 55.2%) were completed between October 2021 and June 2022. Thirty-seven (69.8%) respondents correctly recalled the identified GPV. Discussing results with a genetic counselor (P = .0001), having a GPV related to the cancer/tumor diagnosis (P = .002), and non-Hispanic White race/ethnicity (P = .02) were associated with accurate recall. Twenty-five respondents (47.2%) reported a change in the child's cancer treatment and/or screening recommendations, 17 respondents (32.1%) made a lifestyle change on the basis of the results, and 44 respondents (83.0%) shared results with at least one family member. CONCLUSION: While most respondents remembered that a GPV was identified in the patient, some did not recall having a GPV found, and others recalled germline findings incorrectly. Future work may determine patient/family preferences for timing/method of result return to optimize patient recall and use of germline results.

Multiple TP53 p.R337H haplotypes and implications for tumor susceptibility.

The germline TP53 p.R337H mutation is reported as the most common germline TP53 variant. It exists at a remarkably high frequency in the population of southeast Brazil as founder mutation in two distinct haplotypes with the most frequent co-segregating with the p.E134∗ variant of the XAF1 tumor suppressor and an increased cancer risk. Founder mutations demonstrate linkage disequilibrium with neighboring genetic polymorphic markers that can be used to identify the founder variant in different geographic regions and diverse populations. We report here a shared haplotype among Brazilian, Portuguese, and Spanish families and the existence of three additional distinct TP53 p.R337H alleles. Mitochondrial DNA sequencing and Y-STR profiling of Brazilian carriers of the founder TP53 p.R337H allele reveal an excess of Native American haplogroups in maternal lineages and exclusively European haplogroups in paternal lineages, consistent with communities established through male European settlers with extensive intermarriage with Indigenous women. The identification of founder and independent TP53 p.R337H alleles underlines the importance for considering the haplotype as a functional unit and the additive effects of constitutive polymorphisms and associated variants in modifier genes that can influence the cancer phenotype.

Pathogenic Germline Mutational Landscape in Patients With Renal Cell Carcinoma and Associated Clinicopathologic Features.

PURPOSE: A subset of renal cell carcinoma (RCC) cases occur because of a hereditary predisposition. However, the prevalence and profiling of germline alterations in RCC have not been fully characterized. Additionally, clinicopathologic factors associated with pathogenic or likely pathogenic (P/LP) germline variants in patients with RCC remain poorly understood. METHODS: A retrospective analysis of patients with RCC who underwent genetic evaluation was performed. The frequency of P/LP germline variants and genes was evaluated in this cohort. The association between genetic testing outcomes and clinicopathologic features was also assessed. RESULTS: A total of 321 patients with RCC who had germline testing were identified. Within this cohort, 42 patients (13.1%) had P/LP variants. Genes with the most frequent germline mutations were FLCN (n = 10, 3.1%), SDHB (n = 4, 1.2%), VHL (n = 4, 1.2%), MLH1 (n = 3, 0.9%), and CHEK2 (n = 4, 1.2%). Among patients with P/LP variants, 19 (45.2%) had a potentially targetable mutation. The presence of bilateral or multifocal tumors was associated with P/LP variants (P = .0012 and P = .0098, respectively). Patients who had targeted gene testing had higher rates of P/LP variants compared with multigene panel testing (P = .015). Age and family history of cancers (RCC and non-RCC) did not have any statistically significant association with germline testing outcomes. CONCLUSION: Among patients with RCC, unselected for a known familial predisposition, 13.4% had P/LP variants. Almost half of patients with P/LP variants had a potentially targetable mutation. Targeted gene panel testing is a feasible option for patients, particularly if syndromic features are present. Age and family history were not associated with P/LP variants. Future studies are needed to optimize current genetic evaluation criteria to expand the detection of patients with RCC who may have germline mutations.

Implementation of a dedicated cascade testing clinic for patients at risk for hereditary cancer syndromes.

Cascade testing, the site-specific genetic testing of relatives within families with an inherited condition, is underutilized. Long wait times for appointments in specialty genetics clinics are a known barrier to genetic testing access. In our cancer genetics, New Patient Clinic (NPC), the long wait time for an appointment (on average 5 months for routine referrals), was identified by both providers and patients as a barrier to uptake of cascade testing. Timely testing of at-risk relatives is essential to maximize the benefits of cascade testing and reduce cancer morbidity and mortality. Our objective was to improve access via implementation of a different clinical model that designated appointments for patients seeking cascade testing. A secondary goal was to improve use of genetic counselor time. We implemented a dedicated Cascade Testing Clinic (CTC) with an expedited triaging and unique scheduling model to decrease patient wait time to appointment and optimize clinician time. We report on the process and outcomes here. Between October 2016 and February 2020, the average wait time between referral date and first scheduled appointment date was 46 days for the CTC compared to 144 days for the NPC (p < 0.0001). No-show/cancelation/rescheduling rate was 11.7% in the CTC compared to 29.7% in the NPC (p < 0.0001). Genetic counselors saw approximately twice as many patients per half-day clinic in the CTC compared to the NPC (p < 0.00001). Modifications to clinic staffing and appointment times were made based on provider feedback. Implementation of a dedicated clinic specifically for patients seeking cascade testing significantly shortened wait times for this population, reduced patient drop-off, and improved clinician efficiency. The relatively straightforward indications and generally uncomplicated medical histories made this an ideal population for expedited appointments.

High-fat diet plus HNF1A variant promotes polyps by activating ß-catenin in early-onset colorectal cancer.

The incidence of early-onset colorectal cancer (EO-CRC) is rising and is poorly understood. Lifestyle factors and altered genetic background possibly contribute. Here, we performed targeted exon sequencing of archived leukocyte DNA from 158 EO-CRC participants, which identified a missense mutation at p.A98V within the proximal DNA binding domain of Hepatic Nuclear Factor 1 α (HNF1AA98V, rs1800574). The HNF1AA98V exhibited reduced DNA binding. To test function, the HNF1A variant was introduced into the mouse genome by CRISPR/Cas9, and the mice were placed on either a high-fat diet (HFD) or high-sugar diet (HSD). Only 1% of the HNF1A mutant mice developed polyps on normal chow; however, 19% and 3% developed polyps on the HFD and HSD, respectively. RNA-Seq revealed an increase in metabolic, immune, lipid biogenesis genes, and Wnt/ß-catenin signaling components in the HNF1A mutant relative to the WT mice. Mouse polyps and colon cancers from participants carrying the HNF1AA98V variant exhibited reduced CDX2 and elevated ß-catenin proteins. We further demonstrated decreased occupancy of HNF1AA98V at the Cdx2 locus and reduced Cdx2 promoter activity compared with WT HNF1A. Collectively, our study shows that the HNF1AA98V variant plus a HFD promotes the formation of colonic polyps by activating ß-catenin via decreasing Cdx2 expression.

The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: a retrospective study from a large academic tertiary referral center.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition attributed to pathogenic variants in fumarate hydratase (FH) and presents with cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs) and renal cell cancer (RCC). The objective of this study was to characterize the spectrum of clinical and genetic findings in HLRCC at a large academic tertiary care referral center with a focus on dermatologic manifestations. Fifty-seven patients, 41 female and 16 male, with 27 unique pathogenic or likely-pathogenic FH variants were identified from 38 families. Mean age of HLRCC diagnosis was 44.4 years (range 8-82). CLMs were the primary reason for referral in 49.1% (n=28). CLMs were present in 43/56 patients who underwent full skin examination. Three of these 56 patients were diagnosed with cutaneous leiomyosarcoma. Incidence of ULMs was 37/41 female patients; no uterine leiomyosarcomas were observed. RCC was observed in 6/57 patients (mean age of diagnosis: 47.3 years (range 28-79)). CLMs predated RCC in the 3 patients diagnosed with both. Dermatologists have an opportunity to recognize cutaneous manifestations of HLRCC, including cutaneous leiomyomas and rarely cutaneous leiomyosarcomas, and refer for genetic evaluation to provide definitive diagnosis. Identification of HLRCC can promote family cascade testing and screening for RCC.

The Michigan Genetic Hereditary Testing (MiGHT) study's innovative approaches to promote uptake of clinical genetic testing among cancer patients: a study protocol for a 3-arm randomized controlled trial.

BACKGROUND: Although most cancers are sporadic, germline genetic variants are implicated in 5-10% of cancer cases. Clinical genetic testing identifies pathogenic germline genetic variants for hereditary cancers. The Michigan Genetic Hereditary Testing (MiGHT) study is a three-arm randomized clinical trial that aims to test the efficacy of two patient-level behavioral interventions on uptake of cancer genetic testing. METHODS: The two interventions being tested are (1) a virtual genetics navigator and (2) motivational interviewing by genetic health coaches. Eligible participants are adults with a diagnosis of breast, prostate, endometrial, ovarian, colorectal, or pancreatic cancer who meet the National Comprehensive Cancer Network (NCCN) criteria for genetic testing. Participants are recruited through community oncology practices affiliated with the Michigan Oncology Quality Consortium (MOQC) and have used the Family Health History Tool (FHHT) to determine testing eligibility. The recruitment goal is 759 participants, who will be randomized to usual care or to either the virtual genetics navigator or the motivational interviewing intervention arms. The primary outcome will be the proportion of individuals who complete germline genetic testing within 6 months. DISCUSSION: This study addresses patient-level factors which are associated with the uptake of genetic testing. The study will test two different intervention approaches, both of which can help address the shortage of genetic counselors and improve access to care. TRIAL REGISTRATION: This study has been approved by the Institutional Review Board of the University of Michigan Medical School (HUM00192898) and registered in ClinicalTrials.gov (NCT05162846).

A retrospective cohort study of genetic referral and diagnosis of Lynch syndrome in patients with cutaneous sebaceous lesions.

Immunohistochemistry (IHC) of cutaneous sebaceous lesions (SL) can be used to screen patients for Lynch syndrome (LS). There is little data on rates of genetic referral and outcomes of genetic testing for patients with SL. This single-center retrospective study characterizes 400 + patients with SL, including IHC results, genetics referrals, and outcomes of genetic testing. Retrospective chart reviews were performed for patients with a pathology-confirmed diagnosis of SL at the University of Michigan between January 2009 and December 2019. 447 patients with 473 SL were identified. Excluding 20 patients with known LS, IHC was conducted in 173 (41%) patients. 92/173 (53%) patients had abnormal results. 69 of these 92 (75%) patients were referred to genetics. 32 additional patients were referred with normal IHC (n = 22) or without IHC (n = 10). Of 101 patients referred, 65 (64%) were seen and 47 (47%) completed genetic testing. 7/47 (15%) had pathogenic variants associated with LS, six with concordant abnormal IHC and one without IHC. Cancer genetics referral of patients with SL, particularly for lesions with abnormal IHC, yields a significant rate of LS diagnosis. Providers should consider genetics referral for patients with SL.