| 11. |
- Mantere, Tuomo, et al.
(author)
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Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Journal article (peer-reviewed)abstract
- Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640-644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640-644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.
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| 12. |
- Matejcic, Marco, et al.
(author)
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Germline variation at 8q24 and prostate cancer risk in men of European ancestry
- 2018
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 x 10(-15)), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95% CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for similar to 25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.
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| 13. |
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| 14. |
- Siltanen, Sanna, et al.
(author)
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ARLTS1 germline variants and the risk for breast, prostate, and colorectal cancer
- 2008
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In: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 16:8, s. 983-91
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Journal article (peer-reviewed)abstract
- Recently, a nonsense alteration Trp149Stop in the ARLTS1 gene was found more frequently in familial cancer cases versus sporadic cancer patients and healthy controls. Here, the role of Trp149Stop or any other ARLTS1 germline variant was evaluated on breast, prostate, and colorectal cancer risk. The whole gene was screened for germline alterations in 855 familial cancer patients. The five observed variants were further screened in 1169 non-familial cancer patients as well as in 809 healthy population controls. The Trp149Stop was found at low frequencies (0.5-1.2%) in all patient subgroups versus 1.6% in controls, and the mutant allele did not co-segregate with disease status in families with multiple affected individuals. The CC genotype in the Cys148Arg variant was slightly more common among both familial and sporadic breast (odds ratio (OR), 1.48; 95% confidence interval (CI), 1.16-1.87; P=0.001) and prostate cancer patients (OR, 1.50; 95% CI, 1.13-1.99; P=0.005) when compared to controls. A novel ARLTS1 variant Gly65Val was found at higher frequency among familial prostate cancer patients (8 of 164, 4.9%) than in controls (13 of 809, 1.6%; OR, 3.14; 95% CI, 1.28-7.70, P=0.016). However, after adjusting for multiple testing, none of these results were still significant. No association was found with any of the variants and colorectal cancer risk. Our results suggest that Trp149Stop is not a predisposition allele in breast, prostate, or colorectal cancer in the Finnish population, and, while the Gly65Val variant may increase familial prostate cancer risk and the Cys148Arg change may affect both breast and prostate cancer risk, the evidence is not strong in these data.
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| 15. |
- Sjöblom, Liisa, et al.
(author)
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Microseminoprotein-Beta Expression in Different Stages of Prostate Cancer.
- 2016
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:3
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Journal article (peer-reviewed)abstract
- Microseminoprotein-beta (MSMB, MSMB) is an abundant secretory protein contributed by the prostate, and is implicated as a prostate cancer (PC) biomarker based on observations of its lower expression in cancerous cells compared with benign prostate epithelium. However, as the current literature on MSMB is inconsistent, we assessed the expression of MSMB at the protein and mRNA levels in a comprehensive set of different clinical stages of PC. Immunohistochemistry using monoclonal and polyclonal antibodies against MSMB was used to study protein expression in tissue specimens representing prostatectomies (n = 261) and in diagnostic needle biopsies from patients treated with androgen deprivation therapy (ADT) (n = 100), and in locally recurrent castration-resistant PC (CRPC) (n = 105) and CRPC metastases (n = 113). The transcript levels of MSMB, nuclear receptor co-activator 4 (NCOA4) and MSMB-NCOA4 fusion were examined by qRT-PCR in prostatectomy samples and by RNA-sequencing in benign prostatic hyperplasia, PC, and CRPC samples. We also measured serum MSMB levels and genotyped the single nucleotide polymorphism rs10993994 using DNA from the blood of 369 PC patients and 903 controls. MSMB expression in PC (29% of prostatectomies and 21% of needle biopsies) was more frequent than in CRPC (9% of locally recurrent CRPCs and 9% of CRPC metastases) (p<0.0001). Detection of MSMB protein was inversely correlated with the Gleason score in prostatectomy specimens (p = 0.024). The read-through MSMB-NCOA4 transcript was detected at very low levels in PC. MSMB levels in serum were similar in cases of PC and controls but were significantly associated with PC risk when adjusted for age at diagnosis and levels of free or total PSA (p<0.001). Serum levels of MSMB in both PC patients and controls were significantly associated with the rs10993994 genotype (p<0.0001). In conclusion, decreased expression of MSMB parallels the clinical progression of PC and adjusted serum MSMB levels are associated with PC risk.
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| 16. |
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| 17. |
- Szulkin, Robert, et al.
(author)
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Prediction of individual genetic risk to prostate cancer using a polygenic score.
- 2015
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In: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 75:13, s. 1467-74
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Journal article (peer-reviewed)abstract
- BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction.METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls.RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk.CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
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| 18. |
- Teerlink, Craig C., et al.
(author)
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Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease
- 2014
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In: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 133:3, s. 347-356
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Journal article (peer-reviewed)abstract
- Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p a parts per thousand currency sign 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.
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| 19. |
- Torniainen, Suvi, et al.
(author)
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Lactase persistence, dietary intake of milk, and the risk for prostate cancer in Sweden and Finland.
- 2007
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In: Cancer Epidemiol Biomarkers Prev. - Univ Helsinki, Dept Med Genet, Helsinki 00251, Finland. Univ Helsinki, Cent Hosp, Mol Genet Lab, FIN-00014 Helsinki, Finland. Karolinska Inst, Dept Med Epidemiol & Biostat, S-10401 Stockholm, Sweden. Tampere Univ Hosp, Res Unit, FIN-33521 Tampere, Finland. Tampere Univ Hosp, Dept Clin Chem, FIN-33521 Tampere, Finland. Tampere Univ Hosp, Inst Med Technol, Canc Genet Lab, FIN-33521 Tampere, Finland. Tampere Univ Hosp, Dept Urol, FIN-33521 Tampere, Finland. Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. Univ Milan, Dept Stat, I-20122 Milan, Italy. Univ Umea Hosp, Dept Surg & Perioperat Sci Urol & Androl, S-90185 Umea, Sweden. : AMER ASSOC CANCER RESEARCH. - 1055-9965 .- 1538-7755. ; 16:5, s. 956-61
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Journal article (peer-reviewed)
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| 20. |
- Wahlström, Gudrun, et al.
(author)
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The variant rs77559646 associated with aggressive prostate cancer disrupts ANO7 mRNA splicing and protein expression.
- 2022
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In: Human molecular genetics. - 1460-2083. ; 31:12, s. 2063-2077
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Journal article (peer-reviewed)abstract
- Prostate cancer is among the most common cancers in men, with a large fraction of the individual risk attributable to heritable factors. A majority of the diagnosed cases does not lead to a lethal disease, and hence biological markers that can distinguish between indolent and fatal forms of the disease are of great importance for guiding treatment decisions. Although over 300 genetic variants are known to be associated with prostate cancer risk, few have been associated with the risk of an aggressive disease. One such variant is rs77559646 located in ANO7. This variant has a dual function. It constitutes a missense mutation in the short isoform of ANO7 and a splice region mutation in full-length ANO7. In this study, we have analyzed the impact of the variant allele of rs77559646 on ANO7 mRNA splicing using a minigene splicing assay and by performing splicing analysis with the tools IRFinder (intron retention finder), rMATS (replicate multivariate analysis of transcript splicing) and LeafCutter on RNA sequencing data from prostate tissue of six rs77559646 variant allele carriers and 43 non-carriers. The results revealed a severe disruption of ANO7 mRNA splicing in rs77559646 variant allele carriers. Immunohistochemical analysis of prostate samples from patients homozygous for the rs77559646 variant allele demonstrated a loss of apically localized ANO7 protein. Our study is the first to provide a mechanistic explanation for the impact of a prostate cancer risk SNP on ANO7 protein production. Furthermore, the rs77559646 variant is the first known germline loss-of-function mutation described for ANO7. We suggest that loss of ANO7 contributes to prostate cancer progression.
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