Phillip R. Cooper

Personalized Prostate Specific Antigen Testing Using Genetic Variants May Reduce Unnecessary Prostate Biopsies

PURPOSE Recent studies have identified genetic variants associated with increased serum prostate specific antigen concentrations and prostate cancer risk, raising the possibility of diagnostic bias. By correcting for the effects of these variants on prostate specific antigen, it may be possible to create a personalized prostate specific antigen cutoff to more accurately identify individuals for whom biopsy is recommended. Therefore, we determined how many men would continue to meet common biopsy criteria after genetic correction of their measured prostate specific antigen concentrations. MATERIALS AND METHODS The genotypes of 4 single nucleotide polymorphisms previously associated with serum prostate specific antigen levels (rs2736098, rs10788160, rs11067228 and rs17632542) were determined in 964 healthy Caucasian volunteers without prostate cancer. Genetic correction of prostate specific antigen was performed by dividing an individuals prostate specific antigen value by his combined genetic risk. Analyses were used to compare the percentage of men who would meet commonly used biopsy thresholds (2.5 ng/ml or greater, or 4.0 ng/ml or greater) before and after genetic correction. RESULTS Genetic correction of serum prostate specific antigen results was associated with a significantly decreased percentage of men meeting biopsy thresholds. Genetic correction could lead to a 15% or 20% relative reduction in the total number of biopsies using a biopsy threshold of 2.5 ng/ml or greater, or 4.0 ng/ml or greater, respectively. In addition, genetic correction could result in an 18% to 22% reduction in the number of potentially unnecessary biopsies and a 3% decrease in potentially delayed diagnoses. CONCLUSIONS Our results suggest that 4 single nucleotide polymorphisms can be used to adjust a mans measured prostate specific antigen concentration and potentially delay or prevent unnecessary prostate biopsies in Caucasian men.

Outcomes in patients with Gleason score 8–10 prostate cancer: relation to preoperative PSA level

Study Type – Therapy (case series)

Associations Between iCOGS Single Nucleotide Polymorphisms and Upgrading in Both Surgical and Active Surveillance Cohorts of Men with Prostate Cancer.

BACKGROUND Associations have been documented recently between some of the 23 single nucleotide polymorphisms newly discovered with the Collaborative Oncological Gene-environment Study iCOGS array that indicate prostate cancer (PCa) risk and aspects of disease aggressiveness. The utility of these iCOGS SNPs remains to be determined in active surveillance (AS). OBJECTIVE To determine associations between iCOGS SNPs and upgrading among men who underwent surgical treatment and AS for low-risk PCa. DESIGN, SETTING, AND PARTICIPANTS The genotypes of the 23 iCOGS SNPs were determined for all white subjects with biopsy Gleason score (GS) 6 including 950 men who underwent definitive treatment with surgery and 209 men who elected AS. The clinical and pathologic characteristics were documented for all subjects. OUTCOME MEASURES AND STATISTICAL ANALYSIS Men who underwent surgery were grouped according to their pathologic GS (upgraded was defined as GS ≥7; nonupgraded remained GS 6). Men who were enrolled in AS were also grouped according to their GS on subsequent surveillance biopsies. Statistical analyses were performed comparing the genotypes between the upgraded and nonupgraded groups. RESULTS AND LIMITATIONS Overall, 31% and 34% of men were upgraded in the surgery and AS cohorts, respectively. Three iCOGS SNPs were significantly associated with the risk of upgrading in the surgical cohort. After correction for multiple testing, only rs11568818 on chromosome 11q22 remained significantly associated with upgrading. Assessment of this allele in the AS cohort reveals that it was present at noteworthy higher frequencies in men with high-grade disease on surveillance biopsies compared with nonupgraded men (p=0.003). This study was primarily limited by the homogeneous patient population. CONCLUSIONS This is the first report of a SNP on chromosome 11q22 associated with higher grade disease in a surgical cohort that is also validated for eventual upgrading in a prospective AS cohort. PATIENT SUMMARY We examined the relationship between a group of genetic markers and prostate cancer (PCa) aggressiveness in a group of patients who underwent surgery for PCa and a group of patients who were enrolled in active surveillance. We found that these genetic markers helped predict which patients had more aggressive disease in both groups.

Association of prostate cancer risk alleles with unfavourable pathological characteristics in potential candidates for active surveillance.

Study Type – Prognosis (cohort)

Prostate Cancer Risk Alleles are Associated with Prostate Cancer Volume and Prostate Size

PURPOSE Genome-wide association studies have identified an increasing number of single nucleotide polymorphisms associated with prostate cancer risk. Some of these genetic variants are also associated with serum prostate specific antigen levels and lower urinary tract symptoms, raising the question of whether they are truly prostate cancer biomarkers or simply lead to detection bias. Therefore, we determined whether single nucleotide polymorphisms associated with prostate cancer risk are more strongly associated with tumor or prostate volume. MATERIALS AND METHODS The genotypes of 38 validated prostate cancer risk single nucleotide polymorphisms were determined in 1,321 white men who underwent radical prostatectomy. Univariate and multivariate analyses were performed to compare the relationship of single nucleotide polymorphism frequency with total prostate and tumor volumes. RESULTS On multivariate analysis 2 single nucleotide polymorphisms on chromosome 8q24, rs16901979 (A) and rs6983267 (G), were significantly associated with increased tumor volume (p=0.01 and 0.02, respectively). In contrast, rs17632542 (T) near the PSA gene on 19q13 was associated with significantly lower tumor volume and rs10788160 (A) on 10q26 was associated with significantly larger prostate volume (p=0.02 and 0.01, respectively). CONCLUSIONS Analysis of 38 single nucleotide polymorphisms associated with prostate cancer risk revealed a significant association between several on chromosome 8q24 and increased tumor volume but not prostate volume. This suggests that they are bona fide markers of prostate cancer susceptibility and possibly more aggressive disease. Other prostate cancer risk alleles are associated with prostate specific antigen and increased prostate or decreased tumor volume, suggesting detection bias due to their phenotypic influence.

Prostate Cancer Risk Alleles and Their Associations with Other Malignancies

OBJECTIVE To determine whether certain risk alleles are responsible for the relationship between prostate cancer (CaP) and other malignancies. CaP has been associated with other common malignancies. Recently, numerous single nucleotide polymorphisms (SNPs) have been associated with CaP susceptibility. METHODS We genotyped 1121 patients with CaP for 36 risk alleles known to be significantly associated with CaP susceptibility and determined their relationships to other malignancies in CaP probands and their first-degree relatives. RESULTS The most common other malignancies in the CaP probands were nonmelanoma skin cancer (13.6%), leukemia (7.3%), melanoma (3.9%), non-Hodgkins lymphoma (0.7%), colorectal cancer (0.6%), and multiple myeloma (0.3%). Among the probands, a significantly increased frequency of leukemia was found in the carriers of SNP rs2736098 (5p15, P = .03) and melanoma in the carriers of either SNP rs1512268 (8p21, P = .006) or SNP rs5759167 (22q13, P = .02). Multiple myeloma was more common in carriers of SNP rs9364554 (6q25, P = .02). The probands who were carriers of SNP rs16901979 (8q24) were significantly more likely to report a family history of melanoma (P = .03), and the probands with a family history of multiple myeloma and non-Hodgkins disease were significantly more likely to be carriers of SNP rs12621278 (2q31, P = .04) and rs6465657 (7q21, P = .02), respectively. CONCLUSION Certain alleles associated with CaP susceptibility might be associated with an increased or a decreased risk of other malignancies in CaP probands and their first-degree relatives. Additional studies are warranted to examine the underlying mechanisms of these SNPs in CaP and other malignancies.

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.

Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10−6]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r2 = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10−32) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10−7).

A rare 8q24 single nucleotide polymorphism (SNP) predisposes North American men to prostate cancer and possibly more aggressive disease.

To assess the frequency of a novel prostate cancer‐associated single nucleotide polymorphism (SNP), rs188140481, in a North American population and to evaluate the clinical significance of this variant including annotated prostatectomy pathology.

Genetically adjusted prostate-specific antigen values may prevent delayed biopsies in African-American men

To evaluate whether genetic correction using the genetic variants prostate‐specific antigen (PSA)‐single nucleotide polymorphisms (SNPs) could reduce potentially unnecessary and/or delayed biopsies in African‐American men.

Genetically-Adjusted PSA Values May Prevent Delayed Biopsies in African-American Men

To evaluate whether genetic correction using the genetic variants prostate‐specific antigen (PSA)‐single nucleotide polymorphisms (SNPs) could reduce potentially unnecessary and/or delayed biopsies in African‐American men.