Clonal Hematopoiesis and Mosaicism Revealed by a Multi-Tissue Analysis of Constitutional TP53 Status.

BACKGROUND: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and postzygotic mosaicism (PZM) is critically needed for risk assessment and management. METHODS: Participants in the Li-Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history, and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories. RESULTS: Among 134 participants there was a significant difference for the age at diagnosis (P < 0.001), component cancers (P = 0.007), and clinical testing criteria (P < 0.001), comparing germline with PZM or ACE. ACE panel analysis of DNA from 55 sets of eyebrow follicles (mean 1.4 ug) and 36 formalin-fixed, paraffin imbedded tissues demonstrated low variance (SE, 3%; P = 0.993) for TP53 variant allele fraction, with no significant difference (P = 0.965) between tissue types, and detected CH gene PVs. Of 55 multi-tissue cases, germline status was confirmed for 20, PZM in seven, ACE for 25, and three were indeterminate. Additional CH variants were detected in six ACE and two germline cases. CONCLUSIONS: We demonstrated an effective approach and tools for discerning germline TP53 status. IMPACT: Discernment of PZM and TP53-driven CH increases diagnostic accuracy and enables risk-appropriate care.

Germline mutations and age at onset of lung adenocarcinoma.

BACKGROUND: To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset. METHODS: The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non-FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model. RESULTS: Subjects (n = 187; age, 28-89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack-years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5-20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5-16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, -1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking. CONCLUSIONS: Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high-risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis.

Li-Fraumeni Exploration Consortium Data Coordinating Center: Building an Interactive Web-Based Resource for Collaborative International Cancer Epidemiology Research for a Rare Condition.

BACKGROUND: The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented. METHODS: The Li-Fraumeni Exploration (LiFE) Consortium's DCC was created using multiple open source packages, including LAM/G Application (Linux, Apache, MySQL, Grails), Extraction-Transformation-Loading (ETL) Pentaho Data Integration Tool, and the Saiku-Mondrian client. This document serves as a resource for building a rare disease DCC for multi-institutional collaborative research. RESULTS: The primary scientific and technological objective to create an online central repository into which data from all participating sites could be deposited, harmonized, aggregated, disseminated, and analyzed was completed. The cohort now include 2,193 participants from six contributing sites, including 1,354 individuals from families with a pathogenic or likely variant in TP53. Data on cancer diagnoses are also available. Challenges and lessons learned are summarized. CONCLUSIONS: The methods leveraged mitigate challenges associated with successfully developing a DCC's technical infrastructure, data harmonization efforts, communications, and software development and applications. IMPACT: These methods can serve as a framework in establishing other collaborative research efforts. Data from the consortium will serve as a great resource for collaborative research to improve knowledge on, and the ability to care for, individuals and families with Li-Fraumeni syndrome.

Development and evaluation of a decision aid for BRCA carriers with breast cancer.

BRCA+ breast cancer patients face high risk for a second breast cancer and ovarian cancer. Helping these women decide among risk-reducing options requires effectively conveying complex, emotionally-laden, information. To support their decision-making needs, we developed a web-based decision aid (DA) as an adjunct to genetic counseling. Phase 1 used focus groups to determine decision-making needs. These findings and the Ottawa Decision Support Framework guided the DA development. Phase 2 involved nine focus groups of four stakeholder types (BRCA+ breast cancer patients, breast cancer advocates, and genetics and oncology professionals) to evaluate the DA's decision-making utility, information content, visual display, and implementation. Overall, feedback was very favorable about the DA, especially a values and preferences ranking-exercise and an output page displaying personalized responses. Stakeholders were divided as to whether the DA should be offered at-home versus only in a clinical setting. This well-received DA will be further tested to determine accessibility and effectiveness.

Linkage of a pedigree drawing program and database to a program for determining BRCA mutation carrier probability.

An export module was developed for transferring primary relational pedigree data directly from a widely used pedigree program and relational database to the BRCAPRO program for calculation of BRCA gene mutation probability estimation.

Development of a cancer genetics education program for clinicians.

BACKGROUND: There is a gap in knowledge about hereditary cancer and genetic testing among primary care practitioners. Education is needed to enable identification and management of patients at high risk for cancer. METHODS: A new cancer genetics curriculum was delivered through individual lectures and full-day conferences. Innovative marketing and conference organizational approaches were used to increase participation. RESULTS: The curriculum has been delivered to 7,400 health care professionals with diverse educational backgrounds. CONCLUSION: Conventional formats were successfully used to implement this new curriculum. CME evaluations indicated satisfaction with the programs and a clear need for and continued interest in cancer genetics applications.