Lay understandings of drug-gene interactions: The right medication, the right dose, at the right time, but what are the right words?

As pharmacogenomic (PGx) testing increases in popularity, lay concepts of drug-gene interactions set the stage for shared decision making in precision medicine. Few studies explore what recipients of PGx results think is happening in their bodies when a drug-gene interaction is discovered. To characterize biobank participants' understanding of PGx research results, we conducted a focus group study, which took place after PGx variants conferring increased risk of dihydropyrimidine dehydrogenase (DPD) deficiency were disclosed to biobank contributors. DPD deficiency confers an increased risk of adverse reaction to commonly used cancer chemotherapeutics. Ten focus groups were conducted, ranging from two to eight participants. Fifty-four individuals participated in focus groups. A framework approach was used for descriptive and explanatory analysis. Descriptive themes included participants' efforts to make sense of PGx findings as they related to: (1) health implications, (2) drugs, and (3) genetics. Explanatory analysis supplied a functional framework of how participant word choices can perform different purposes in PGx communication. Results bear three main implications for PGx research-related disclosure. First, participants' use of various terms suggest participants generally understanding their PGx results, including how positive PGx results differ from positive disease susceptibility genetic results. Second, PGx disclosure in biobanking can involve participant conflation of drug-gene interactions with allergies or other types of medical reactions. Third, the functional framework suggests a need to move beyond a deficit model of genetic literacy in PGx communication. Together, findings provide an initial evidence base for supporting bidirectional expert-recipient PGx results communication.

Patient-reported anticipated barriers and benefits to sharing cancer genetic risk information with family members.

While prior studies have largely focused on family communication of diagnostic single-gene test results or specific types of cancer testing results, far less work has investigated family communication of cancer-related genetic results that include multi-gene panels, a broad array of cancer types/stages, and participants without family history of cancer. The study we report here examined individuals' anticipated barriers and benefits to sharing genetic information with family members. An 80+ gene panel was performed on participants recruited from Mayo Clinic, diagnosed with different cancer types, who did not have a family history suggestive of an inherited risk. Participants completed a 49-item survey before receiving genetic test results. Family variant testing was provided to family members at no cost, allowing factors influencing intent to share to be examined in the absence of financial burdens. In all, 1721 of 2984 individuals who received genetic testing completed the survey (57.7% completion rate). Participants' intent to share with parents, siblings, and children was inversely related to the number of anticipated barriers to sharing and directly related to the number of anticipated benefits to sharing. Of those participants who did not intend to share with parents, siblings, and adult children, 64.8%, 30.3%, and 67.6% reported that there were no barriers, while 17.1%, 24.5%, and 40.2.% reported there were no benefits. Findings indicate that barriers to sharing genetic information with family members vary across family member types, and an inability to identify at least one benefit of sharing with family members is a predictor of intent not to share.

Factors that Influence Intent to Share Genetic Information Related to Cancer Risk with Family Members.

We describe factors influencing patient decisions to share positive cancer genetic test results with family members. We focused on patients who were diagnosed with several different cancer types but did not have a family history that was suggestive of an inherited risk. Participants were recruited from Mayo Clinic and had been recently diagnosed with cancer. An 80+ gene panel was performed. Before receiving genetic test results, patients completed a 49-item survey on their intent to share their results with relatives. 1,721 (57.7%) of 2,984 individuals who elected to pursue genetic testing completed the survey. Most patients planned to share cancer-related genetic results with a spouse or partner (97.0%), at least one adult child (92.2%), at least one sibling (86.2%), and with at least one parent (70.3%). Familial support scores and familial communication scores were predictive of intent to share cancer-related genetic test results. Our data highlight differences in family communication capacity and support that are important for clinicians to consider when supporting patients who wish to share cancer-related genetic test results with family members. Our data point to several potential interventional strategies that might increase the likelihood of cancer-related genetic test results being shared with family members at risk.

Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19.

Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.

B Cells Drive Autoimmunity in Mice with CD28-Deficient Regulatory T Cells.

Follicular regulatory T (TFR) cells are a newly defined regulatory T cell (Treg) subset that suppresses follicular helper T cell-mediated B cell responses in the germinal center reaction. The precise costimulatory signal requirements for proper TFR cell differentiation and function are still not known. Using conditional knockout strategies of CD28, we previously demonstrated that loss of CD28 signaling in Tregs caused autoimmunity in mice (termed CD28-ΔTreg mice), characterized by lymphadenopathy, accumulation of activated T cells, and cell-mediated inflammation of the skin and lung. In this study, we show that CD28 signaling is required for TFR cell differentiation. Treg-specific deletion of CD28 caused a reduction in TFR cell numbers and function, which resulted in increased germinal center B cells and Ab production. Moreover, residual CD28-deficient TFR cells showed a diminished suppressive capacity as assessed by their ability to inhibit Ab responses in vitro. Surprisingly, genetic deletion of B cells in CD28-ΔTreg mice prevented the development of lymphadenopathy and CD4+ T cell activation, and autoimmunity that mainly targeted skin and lung tissues. Thus, autoimmunity occurring in mice with CD28-deficient Tregs appears to be driven primarily by loss of TFR cell differentiation and function with resulting B cell-driven inflammation.