Genetic Correction of PSA Values Using Sequence Variants Associated with PSA Levels

Abstract

Measuring serum levels of the prostate specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. In order to search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and SNPs at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 (rs17632542 (KLK3: I179T), each with Pcombined < 3×10−10. Among 3,834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (OR between 1.15 and 1.27). Assessment of association between the 6 loci and prostate cancer risk in 5,325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the US showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other 4 loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.

TERT rs2736098 Polymorphism and Cancer Risk: Results of a Meta-analysis

“…Furthermore, two articles lacking usable data were not used in our meta-analysis. One article studying 5009 cases and 41334 controls showed that the TERT rs2736098 polymorphism is associated with prostate cancer (Gudmundsson et al, 2010), The other article studied 11290 cancer patients and 31162 controls and showed that TERT rs2736098 A variant genotypes are associated with significant increases in risk for basal cell carcinoma, lung cancer, bladder cancer and prostate cancer but not of cervical cancer in the European population.…”

“…A summary of the individual studies is shown in Table 1. Two studies (Rafnar et al,2009;Gudmundsson et al, 2010) were not included in our meta-analysis for reasons outlined in the Discussion section.…”

Variants at IRX4 as prostate cancer expression quantitative trait loci

“…26,27 For each SNP not present on the Affymetrix 6.0 array, pairwise linkage disequilibrium (LD), as measured by r 2 , was computed using genotype data from residents of Utah with northern and western European ancestry (HapMap3 CEU population; Altshuler et al; 28 http://hapmap.ncbi.nlm.nih.gov/). For each SNP, the SNP on the Affymetrix 6.0 array with the strongest LD was selected as the tag SNP.…”

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

“…2,[5][6][7][8][9][10][11] The genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) gene regions could play a role in MM etiology for two reasons: first the two genes are responsible for crucial cellular processes, namely telomere homeostasis, second their polymorphic variants have been found to be associated with multiple cancer types and other human phenotypes. [12][13][14][15][16][17][18][19][20][21][22][23][24] TERT and TERC constitute the telomerase complex, 25 whose correct functioning is fundamental for the accurate de novo synthesis of telomeric ends. Even moderate changes in TERT and TERC activity could profoundly affect telomere homeostasis.…”

“…12,14,15 In addition, TERT polymorphisms are associated with other human phenotypes such as pulmonary fibrosis and PSA levels. [22][23][24]34 A very recent GWAS has reported the association of rs10936599 with increased risk of MM. 7 This polymorphism lies in 3q26.2, in a linkage disequilibrium (LD) region that includes also the TERC gene.…”