SALT LAKE CITY — The Healthy Oregon Project (HOP), a free statewide genetic screening effort, has identified about 500 Oregonians at increased risk of developing cancer or familial hypercholesterolemia (FH).
HOP, which began in 2018, aims to perform germline sequencing on thousands of individuals living in Oregon to develop a cost-effective screening test for inherited genetic disorders and establish a repository of patient information to enable future research as well as identify participants who may be at increased risk of developing cancer or heart disease. More than 17,000 HOP participants have undergone screening in its first four years.
"Overall, we have impacted more than 500 participants in Oregon by providing them with this health information to let them go on and take charge of their health and get recommendations and screening guidelines needed to manage their care," Timothy O'Brien, assistant staff scientist at the Knight Diagnostic Laboratories at Oregon Health and Sciences University in Portland, said when he presented the results at this year's American College of Medical Genetics and Genomics (ACMG) annual meeting here.
Oregonians were recruited to HOP at OHSU as well as at statewide events and were enrolled and consented via a HIPAA-compliant app. Participants then sent in saliva samples for DNA sequencing at OHSU and were asked to participate in surveys about their lifestyle, behavior, stress, and more. Participants were an average of 47 years old, mostly white, and more likely to be women.
The HOP researchers initially focused on identifying individuals with rare hereditary cancer disorders like hereditary breast and ovarian cancer (HBOC) syndrome or Lynch syndrome using a 25-gene panel. They later expanded to a 32-gene panel that also aimed to identify people with FH. In addition to BRCA1, BRCA2, PALB2, TP53, and LDLR, the panel includes RB1, SMAD4, PTEN, and others, and overlaps with the ACMG secondary findings gene list.
Negative results, which O'Brien said they defined as uncovering no pathogenic or likely pathogenic germline variants, were reported back to participants through the app. No variants of uncertain significance (VUS) or copy-number variants were typically returned.
Anyone with a positive result — where a pathogenic or likely pathogenic germline variant was found —was asked to provide a second saliva sample for confirmatory Sanger sequencing. If confirmed, a positive result was entered into the participant's medical record and the individual would be contacted by a genetic counselor to discuss the result and any recommendations.
Across their cohort, the HOP researchers identified at some point a pathogenic or likely pathogenic variant in about 75 percent of the genes on their panel. CHEK2 was found to have the most pathogenic or likely pathogenic variants, and frameshift variants were the most common variants observed overall, followed by nonsense and missense variants.
For hereditary cancer genes, the screening program had a 5 percent positive rate. For HBOC in particular, there was a 0.72 percent positive rate, while for Lynch syndrome, there was a 0.39 percent positive rate. O'Brien pointed out that they detected the most Lynch syndrome-linked variants in PMS2 and the fewest in MLH1, which he said was the reverse of what they expected based on past results, though is similar to more recent studies.
Meanwhile, for FH, they reported a 0.34 percent positive rate. O'Brien noted that the prevalence of FH varies among populations, but a recent analysis suggested an overall prevalence of 0.32 percent.
Within their cohort, O'Brien and his colleagues also noted a number of variants that were predicted to affect RNA splicing. They elected to modify their protocol to further explore these variants and asked participants with them to supply a blood sample for RNA sequencing analysis. Seven participants provided such samples.
Five of the seven predictions of an effect on RNA splicing were correct, and those individuals received positive reports. For another individual, the prediction was incorrect and that person received a negative report. In the remaining sample, splicing was altered but through a complex mechanism, leading the researchers to deem it a VUS. This, O'Brien noted, was the only VUS the study has reported out.
He added that they did find that implementing RNA studies as part of HOP was useful to determine the effect of certain variants, though it came with increased cost and difficulty, as participants had to have blood drawn. "For that reason, we think RNA studies are useful in population screening," O'Brien said, adding, though, that they might not work for all low-cost screening programs.