Genetic Factors associated with Conversion from Active Surveillance to Treatment for Prostate Cancer

This is a genome-wide association study (GWAS) of conversion from active surveillance (AS) for prostate cancer (PC) to treatment. AS is the monitoring with screening tests and/or biopsies over time of men usually with low-risk, early-stage PC to avoid harmful side effects of PC treatment. "Conversion" refers to patients who withdraw from AS (switch to active treatment) due to changes in their cancer development, anxiety about delayed treatment, or other reasons. Patients who converted because of anxiety alone were censored in the GWAS analysis. The overall goal of this study is to develop an easily measurable, germline-based panel of genetic variants to aid in selecting PC patients appropriate for AS and/or the intensity of monitoring. In total, 6,324 PC patients from 28 collaborating institutions are included in this study. Patients are those with PC who are either on AS or who have previously converted from AS to treatment. In this study, 70% of all subjects were diagnosed with very low-risk, low-risk, or low-volume intermediate-risk PC (Kryvenko and Epstein, 2016; PMID: 26709152) and have been enrolled in an AS program. DNA was extracted from blood, saliva, or formalin-fixed, paraffin-embedded (FFPE) tissue collected from the study subjects at the participating sites. Genotyping, quality control processes, and imputation were performed at the Center for Inherited Disease Research (CIDR) at Johns Hopkins University. CIDR used the Illumina Infinium Multi-Ethnic Global Array (MEGA) version 1, which included genome-wide tag SNPs and 10,000 SNPs selected with custom content. Quality control and assurance (QC/QA) checks on genotyped data involved four domains: sample-level checks, batch effects, SNP-level checks, and preliminary association tests. Samples and SNPs passing the QC/QA checks were imputed to appropriate reference panels (HRC r1.1 for patients of European ancestry) using the Michigan Imputation Server (PMID: 27571263). Unmeasured genetic variants were imputed using the Trans-Omics for Precision Medicine (TOPMed) Imputation Server, with 97,256 reference samples and 308,107,085 SNPs. Variants with imputation quality (INFO) score < 0.3 were excluded, leaving a total of 22,691,641 SNPs successfully imputed. After QC steps, a total of 5,936 samples genotyped at CIDR remained for inclusion in the GWAS.]]>
Inclusion Criteria and prostate cancer patients who primarily met the following traditional active surveillance criteria:

Diagnosed with prostate cancer
Gleason ≤ 3+3 prostate cancer, with exceptions (see below)
≤ 3 cores involved with cancer, with exceptions (see below)
≥ 50% of any 1 core involved with prostate cancer, with exceptions (see below)
Age > 18 years old

Exclusion Criteria:

Men not diagnosed with prostate cancer
Prostate cancer patients with a Gleason score out of the range of 3+4, with exceptions (see below)
Patients with more than 3 cores involved with cancer, with exceptions (see below)
Patients under 18 years old

Note: Patients who may not meet the above criteria for pathology results, but who are > 18 years old and diagnosed with prostate cancer and whose prostate cancer disease was being followed by active surveillance may still be included.Exceptions: Most men had low-risk PC (3,639, 70%) and/or features of low-risk, low-volume disease: GG1 (4,819, 92%), 1-2 positive biopsy cores (4,113, 79%), and a median PSA at diagnosis of 5 ng/mL. Using genetic information to infer ancestry, 88% were classified as European ancestry. Baseline characteristics were missing for the following proportion of study participants: age at diagnosis (<0.1%), GG group (<0.1%), PSA concentration (3.3%), clinical tumor stage (6.9%), number of positive biopsy cores (2.5%), and risk-group classification (<0.1%). ]]>
August 2015: Project started. The lead study investigators are located at the Northwestern University Feinberg School of Medicine (PI: Catalona), the NorthShore University Health System (Co-I: Helfand), and the University of California, San Francisco (Co-I: Witte). April 2018: MEGA array custom content selected. January 2020: Completed collection of DNA samples from men on AS for prostate cancer (6,335 subjects) from 28 collaborating sites (US, Canada, Australia, and the Netherlands); samples genotyped and quality assurance/quality control (QA/QC) steps performed; more than 90% of phenotype data collected from sites.April 2020: All the phenotype data collected from sites.June 2021: Descriptive manuscript accepted by the Journal of Urology.August 2021: GWAS manuscript submitted for publication. Funding: This study was funded by a National Cancer Institute SPORE grant (P50-CA180995; PI: Catalona). Dr. Catalona also received a CIDR award (X01HG009642) for patient DNA sample genotyping. In addition, he has secured and used > $100,000 in supplemental philanthropic funds each from his Urological Research Foundation and from the NorthShore University Health System Foundation.]]>