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Prostate cancer disproportionately affects men of African ancestry at nearly twice the rate of men of European ancestry despite the advancement of treatment strategies and prevention. In this review, we discuss the underlying causes of these disparities including genetics, environmental/behavioral, and social determinants of health while highlighting the implications and challenges that contribute to the stark underrepresentation of men of African ancestry in clinical trials and genetic research studies. Reducing prostate cancer disparities through the development of personalized medicine approaches based on genetics will require a holistic understanding of the complex interplay of non-genetic factors that disproportionately exacerbate the observed disparity between men of African and European ancestries.

Purpose: The purpose of this study was to perform genetic linkage analysis and association analysis on exome genotyping from highly aggregated African American families with nonpathogenic myopia. African Americans are a particularly understudied population with respect to myopia. Methods: One hundred six African American families from the Philadelphia area with a family history of myopia were genotyped using an Illumina ExomePlus array and merged with previous microsatellite data. Myopia was initially measured in mean spherical equivalent (MSE) and converted to a binary phenotype where individuals were identified as affected, unaffected, or unknown. Parametric linkage analysis was performed on both individual variants (single-nucleotide polymorphisms [SNPs] and microsatellites) as well as gene-based markers. Family-based association analysis and transmission disequilibrium test (TDT) analysis modified for rare variants was also performed. Results: Genetic linkage analysis identified 2 genomewide significant variants at 7p15.2 and 7p14.2 (in the intergenic region between MIR148A and NFE2L3 and in the noncoding RNA LOC401324) and 2 genomewide significant genes (CRHR2 and AVL9) both at 7p14.3. No genomewide results were found in the association analyses. Conclusions: This study identified a significant linkage peak in African American families for myopia at 7p15.2 to 7p14.2, the first potential risk locus for myopia in African Americans. Interesting candidate genes are located in the region, including PDE1C, which is highly expressed in the eyes, and known to be involved in retinal development. Further identification of the causal variants at this linkage peak will help elucidate the genetics of myopia in this understudied population.

Purpose: Prostate cancer is the most common cancer in males, with a ~1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ~33% of the familial risk. A portion of the undefined risk may be due to rare susceptibility variants. The African American Hereditary Prostate Cancer (AAHPC) Study, established in 1997, enrolled 77 African American families from seven clinical sites across the United States. The aim of this study is to identify rare, predictive, deleterious variants through exome sequencing of 99 cases from families selected from the AAHPC families and three 1000 Genome controls. Methods: To explore the contribution of rare variation in coding regions to prostate cancer risk, we sequenced the exomes of 99 AAHPC cases at a mean coverage of 30x. Post-variant calling quality control (QC) was implemented using Golden Helix SVS 8 software with filters set for removal of variants with Read Depth >10, Quality Score >10, and Quality Score: Read Depth Ratio > 0.5. Mendelian inconsistency was checked using PLINK. Prioritization of all candidate genes/variants was evaluated using online databases 1000 Genome and bioinformatics tool ANNOVAR for non-reference allele frequency and predictions of functional impact. Conclusions: Through exome sequencing of 99 AAHPC cases and three 1000 Genome controls, we identified 37 nonsynonymous single-nucleotide variants that are considered damaging by at least one predictive scoring tool in our candidate genes. Interesting candidate variants were found in known cancer susceptibility loci BRCA2, MSR1, PCNT, STAT3, WRN and ZFHX3. Future results are pending additional QC and analyses to determine which variants are shared by related individuals within each family compared to those not seen in the controls. Citation Format: Deyana D. Lewis, Shukmei Wong, Angela S. Baker, Joan E. Bailey-Wilson, John D. Carpten, Cheryl D. Cropp. Deleterious coding variants in African American Hereditary Prostate Cancer Study (AAHPC) families [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C050.

Purpose To determine genetic linkage between myopia and Han Chinese patients with a family history of the disease. Methods One hundred seventy-six Han Chinese patients from 34 extended families were given eye examinations, and mean spherical equivalent (MSE) in diopters (D) was calculated by adding the spherical component of the refraction to one-half the cylindrical component and taking the average of both eyes. The MSE was converted to a binary phenotype, where all patients with an MSE of -1.00 D or less were coded as affected. Unaffected individuals had an MSE greater than 0.00 D (ages 21 years and up), +1.50 (ages 11–20), or +2.00 D (ages 6–10 years). Individuals between the given upper threshold and −1.00 were coded as unknown. Patients were genotyped on an exome chip. Three types of linkage analyses were performed: single-variant two-point, multipoint, and collapsed haplotype pattern (CHP) variant two-point. Results The CHP variant two-point results identified a significant peak (heterogeneity logarithm of the odds [HLOD] = 3.73) at 10q26.13 in TACC2. The single-variant two-point and multipoint analyses showed highly suggestive linkage to the same region. The single-variant two-point results identified 25 suggestive variants at HTRA1, also at 10q26.13. Conclusions We report a significant genetic linkage between myopia and Han Chinese patients at 10q26.13. 10q26.13 contains several good candidate genes, such as TACC2 and the known age-related macular degeneration gene HTRA1. Targeted sequencing of the region is planned to identify the causal variant(s).

Purpose: Prostate cancer is the most common cancer in males, but also exhibits a ∼1.5-2-fold higher incidence in African American men compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ∼33 % of the familial risk. A portion of the undefined risk may be due to rare susceptibility variants. The African American Hereditary Prostate Cancer (AAHPC) Study, established in 1997, enrolled 77 AA families from seven clinical sites across the United States (Ann Epidemiol, 2000). The aim of this study is to identify rare, predictive, deleterious variants through exome sequencing of 99 cases from 26 families selected from the AAHPC families (2 to 3 affected men sequenced per family) and three female 1000 Genome controls. Methods: To explore the contribution of rare variation in coding regions of 38 known cancer-causing genes to prostate cancer risk (PCa), we sequenced the exomes of 99 AAHPC cases at a mean coverage of 30x. Post-variant calling quality control (QC) was implemented using Golden Helix SVS 8 software with filters set for removal of variants with Read Depth >10, Quality Score >10, and Quality Score: Read Depth Ratio > 0.5. Mendelian inconsistency was checked using PLINK. Prioritization of all candidate genes/variants were evaluated using online databases including 1000 Genomes and ANNOVAR for non-reference allele frequency and predictions of functional impact. Conclusions. Through exome sequencing of 99 AAHPC cases and 3 female 1000 Genome controls, we identified 37 non-synonymous single nucleotide variants that are considered damaging by at least one predictive scoring tool in our 38 candidate genes. However, most of these variants were common and thus unlikely to be causal. We observed three rare variants that were considered damaging by three predictive scoring tools in two known PCa genes, PCNT and ZFHX3. These 3 variants were each observed in a single different family (in 1 of 3 affected individuals). Interesting rare candidate variants (MAF ≤ 0.01) rs190517526 & rs114692729 were found in known cancer susceptibility loci (CD82 and EZH2). The CD82 variant was observed in all 3 sequenced affecteds in one family and the EZH2 variant was observed in 2 of 3 sequenced affecteds in a different family. These predicted damaging variants in these four genes represent potentially novel causal candidates for some of the 26 AAHPC families sequenced here. Future work will carefully analyze the remainder of the genome in the other 21 sequenced families including planned sequencing of additional family members. Citation Format: Deyana D. Lewis, Shukmei Wong, Angela S. Baker, Isaac Powell, John D. Carpten, Joan E. Bailey-Wilson, Cheryl Cropp. Rare candidate variants shared among affected family members in the African American Hereditary Prostate Cancer Study families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4240.

Family-based study designs are again becoming popular as new next-generation sequencing technologies make whole-exome and whole-genome sequencing projects economically and temporally feasible. Here we evaluate the statistical properties of linkage analyses and family-based tests of association for the Genetic Analysis Workshop 17 mini-exome sequence data. Based on our results, the linkage methods using relative pairs or nuclear families had low power, with the best results coming from variance components linkage analysis in nuclear families and Elston-Stewart model-based linkage analysis in extended pedigrees. For family-based tests of association, both ASSOC and ROMP performed well for genes with large effects, but ROMP had the advantage of not requiring parental genotypes in the analysis. For the linkage analyses we conclude that genome-wide significance levels appear to control type I error well but that “suggestive” significance levels do not. Methods that make use of the extended pedigrees are well powered to detect major loci segregating in the families even when there is substantial genetic heterogeneity and the trait is mainly polygenic. However, large numbers of such pedigrees will be necessary to detect all major loci. The family-based tests of association found the same major loci as the linkage analyses and detected low-frequency loci with moderate effect sizes, but control of type I error was not as stringent.

In experiments on the kinetics of the peroxidase−oxidase oscillatory reaction in pH 5.l acetate buffer, biofilms form in less than 48 h on the quartz reactor surface. The nominally homogeneous peroxidase system shows dynamical changes in response to this biofilm growth, partially explaining subtle differences among dynamics observed over time and between laboratories. Kinetics data and model computations are correlated with micrographs of biofilm formation. It is evident that bare quartz also interacts with reaction species, so that the surface area-to-volume ratio is an important parameter on which observed dynamics depend.