Public perception of predictive cancer genetic testing and research in Oregon.

The potential for using widespread genetic testing to inform health care has become a viable option, particularly for heritable cancers. Yet, little is known about how to effectively communicate the benefits and risks of both personal genetic testing and participation in biorepositories that aid scientific advancements. Nationwide efforts are engaging communities in large genetic studies to better estimate the population-wide prevalence of heritable cancers but have been met with hesitance or declination to participate in some communities. To successfully engage an Oregon population in longitudinal research that includes predictive genetic testing for pathogenic or likely pathogenic variants associated with an increased risk for cancer, researchers conducted 35 focus groups (two of which were held in Spanish) in 24 of Oregon's 36 counties to better understand knowledge and attitudes related to genetic testing and willingness to participate in longitudinal genetic research. A total of 203 adults (mean = 45.6 years; range 18-88), representing a range of education levels and prior knowledge of genetic research, participated in the focus groups. The majority (85%) of participants reported personal or family diagnoses of cancer (e.g., self, family, friends). A majority (87%) also reported a strong interest in cancer genetic testing and receiving genetic information about themselves. Nearly all focus groups (94%, 33 of 35 sites) included participant discussion citing their families (e.g., children, close relatives, and extended family members) as key motivators for participation in genetic research. For example, participants reported interest in increasing personal knowledge about their own and their families' cancer risks in order to respond proactively, if a pathogenic variant was found. While most focus groups (94%, 33 of 35 sites) included participant discussion describing barriers to predictive genetic, testing such as concerns about outcomes, the desire to learn about health risks in oneself mitigated or outweighed those fears for many participants. Other commonly reported concerns were related to potential mistrust of insurance companies, researchers, or institutions, or lack of knowledge about genetics, genetic testing, or genetic research. Participants, particularly in rural areas, highlighted critical factors for research recruitment, such as trust, personal interaction, public education about genetic research, and clear communication about study goals and processes. Our statewide findings reflect that public interest in predictive cancer genetic testing and cancer genetic research can surpass lack of knowledge of the complex topics, particularly when benefits for self and family are emphasized and when study considerations are well articulated.

Hepatocytes from wild-type or heterozygous donors are equally effective in achieving successful therapeutic liver repopulation in murine phenylketonuria (PKU).

Successful restoration of phenylalanine (Phe) clearance following liver-directed gene therapy in murine phenylketonuria (PKU) is likely dependent upon both the number of cells successfully transduced and the amount of phenylalanine hydroxylase (PAH) activity expressed per cell. At low levels of transduction, Phe clearance could be limited by the low absolute number of PAH-expressing cells rather than the total amount of PAH activity produced in the liver. We have evaluated the interrelationship between the number of PAH positive cells, the amount of PAH activity produced and Phe clearance through experiments with hepatocyte-mediated therapeutic liver repopulation in the Pah(enu2) mouse, a model of PKU. We compared the therapeutic efficacy of transplantation with either wild-type hepatocytes or hepatocytes from heterozygous Pah(enu2/+) donors into PAH deficient, hyperphenylalaninemic Pah(enu2)/Pah(enu2) mice. The recipient mice were also homozygous for fumarylacetoacetate hydrolase (FAH) deficiency. In this model system, FAH positive donor hepatocytes enjoy a selective growth advantage in the FAH-deficient recipient. If Phe clearance is governed predominantly by the total PAH activity, then more heterozygous cells, which express lower PAH activity than wild-type cells, should be required to correct Phe clearance. If the absolute donor cell number is more important, then wild-type hepatocytes should have no advantage over heterozygous cells. We successfully carried out therapeutic liver repopulation with heterozygous donor cells in fifteen mice and an additional thirteen transplants with wild-type cells. Blood Phe was successfully reduced in both transplant groups, and the relationship between the final blood Phe level and the extent of liver repopulation with donor cells did not differ between the two donor groups. Regardless of the type of donor cell, liver repopulation of approximately 3-10% was sufficient to at least partially reduce blood phenylalanine, and blood Phe levels were completely corrected in mice that had attained greater than approximately 10% liver repopulation. We conclude from our study that the absolute number of PAH-expressing cells likely governs Phe clearance at least at the levels of repopulation reported here and that the amount of PAH activity per donor cell is a less critical variable. The implication for liver-directed gene therapy of PKU is that only partial correction of cellular PAH deficiency may yet improve Phe clearance as long as a sufficient number of hepatocytes is successfully transduced.