Metabolomic Biomarkers of Prostate Cancer: Prediction, Diagnosis, Progression, Prognosis, and Recurrence

Metabolite profiling is being increasing employed in the study of prostate cancer as a means of identifying predictive, diagnostic, and prognostic biomarkers. This review provides a summary and critique of the current literature. Thirty-three human case-control studies of prostate cancer exploring disease prediction, diagnosis, progression, or treatment response were identified. All but one demonstrated the ability of metabolite profiling to distinguish cancer from benign, tumor aggressiveness, cases who recurred, and those who responded well to therapy. In the subset of studies where biomarker discriminatory ability was quantified, high AUCs were reported that would potentially outperform the current gold standards in diagnosis, prognosis, and disease recurrence, including PSA testing. There were substantial similarities between the metabolites and the associated pathways reported as significant by independent studies, and important roles for abnormal cell growth, intensive cell proliferation, and dysregulation of lipid metabolism were highlighted. The weight of the evidence therefore suggests metabolic alterations specific to prostate carcinogenesis and progression that may represent potential metabolic biomarkers. However, replication and validation of the most promising biomarkers is currently lacking and a number of outstanding methodologic issues remain to be addressed to maximize the utility of metabolomics in the study of prostate cancer.National Institutes of Health (U.S.) (Grant P01 CA055075)National Institutes of Health (U.S.) (Grant CA133891)National Institutes of Health (U.S.) (Grant CA141298)National Institutes of Health (U.S.) (Grant CA136578)National Institutes of Health (U.S.) (Grant UM1 CA167552

Seasonal variability of water mass distribution in the southeastern Beaufort Sea determined by total alkalinity and delta O-18

ISI Document Delivery No.: 903QF Times Cited: 10 Cited Reference Count: 120 Cited References: AAGAARD K, 1981, DEEP-SEA RES, V28, P529, DOI 10.1016/0198-0149(81)90115-1 Alkire MB, 2006, J GEOPHYS RES-OCEANS, V111, DOI 10.1029/2005JC003446 ANDERSON LG, 1990, J GEOPHYS RES-OCEANS, V95, P1703, DOI 10.1029/JC095iC02p01703 Anderson LG, 2001, POLAR RES, V20, P225, DOI 10.1111/j.1751-8369.2001.tb00060.x Anderson LG, 2004, J GEOPHYS RES-OCEANS, V109, DOI [10.1029/2003JC002120, 10.1029/2003JC001773] [Anonymous], 2008, CLIM CHANG 2007 SYNT Arrigo KR, 2004, GEOPHYS RES LETT, V31, DOI 10.1029/2003GL018978 Arrigo KR, 2008, GEOPHYS RES LETT, V35, DOI 10.1029/2008GL035028 Barber DG, 2004, J GEOPHYS RES-OCEANS, V109, DOI 10.1029/2003JC002027 Bates NR, 2009, BIOGEOSCIENCES, V6, P2433 Bauch D, 2005, GLOBAL PLANET CHANGE, V48, P165, DOI 10.1016/j.gloplacha.2004.12.011 Benner R, 2004, GEOPHYS RES LETT, V31, DOI 10.1029/2003GL019251 Bidleman TF, 2007, ENVIRON SCI TECHNOL, V41, P2688, DOI 10.1021/es062375b BYRNE RH, 1987, ANAL CHEM, V59, P1479, DOI 10.1021/ac00137a025 Cai WJ, 2010, SCIENCE, V329, P556, DOI 10.1126/science.1189338 CARMACK EC, 1989, J GEOPHYS RES-OCEANS, V94, P18043, DOI 10.1029/JC094iC12p18043 Carmack EC, 2004, MAR ECOL PROG SER, V277, P37, DOI 10.3354/meps277037 Carmack EC, 2002, ARCTIC, V55, P29 CLAYTON TD, 1993, DEEP-SEA RES PT I, V40, P2115, DOI 10.1016/0967-0637(93)90048-8 Cooper LW, 1997, J GEOPHYS RES-OCEANS, V102, P12563, DOI 10.1029/97JC00015 Cooper LW, 2008, GEOPHYS RES LETT, V35, DOI 10.1029/2008GL035007 Cooper LW, 2005, J GEOPHYS RES-BIOGEO, V110, DOI 10.1029/2005JG000031 Delille B, 2007, LIMNOL OCEANOGR, V52, P1367, DOI 10.4319/lo.2007.52.4.1367 Dickson A. G., 1994, ORNLCDIAC74 DEP EN DICKSON AG, 1990, J CHEM THERMODYN, V22, P113, DOI 10.1016/0021-9614(90)90074-Z DICKSON AG, 1987, DEEP-SEA RES, V34, P1733, DOI 10.1016/0198-0149(87)90021-5 Eicken H, 2002, J GEOPHYS RES-OCEANS, V107, DOI 10.1029/2000JC000583 Ekwurzel B, 2001, J GEOPHYS RES-OCEANS, V106, P9075, DOI 10.1029/1999JC000024 Else BGT, 2011, J GEOPHYS RES-OCEANS, V116, DOI 10.1029/2010JC006760 EPSTEIN S, 1953, GEOCHIM COSMOCHIM AC, V4, P213, DOI 10.1016/0016-7037(53)90051-9 Fransson A, 2009, CONT SHELF RES, V29, P1317, DOI 10.1016/j.csr.2009.03.008 Gibson JAE, 1999, MAR CHEM, V66, P187, DOI 10.1016/S0304-4203(99)00040-7 Grasshoff K., 1983, METHODS SEAWATER ANA Gratton Y., 2006, 2006 GEN M CAN ARCT Guay CK, 1997, DEEP-SEA RES PT II, V44, P1543, DOI 10.1016/S0967-0645(97)00066-0 Guay CKH, 2009, J GEOPHYS RES-OCEANS, V114, DOI 10.1029/2008JC005099 Guo LD, 2007, GEOPHYS RES LETT, V34, DOI 10.1029/2007GL030689 Howell SEL, 2009, GEOPHYS RES LETT, V36, DOI 10.1029/2009GL037681 Jeansson E, 2008, PROG OCEANOGR, V78, P12, DOI 10.1016/j.pocean.2007.08.031 JOHNSON KM, 1993, MAR CHEM, V44, P167, DOI 10.1016/0304-4203(93)90201-X JONES EP, 1981, J GEOPHYS RES-OC ATM, V86, P1041, DOI 10.1029/JC086iC11p11041 JONES EP, 1986, J GEOPHYS RES-OCEANS, V91, P759, DOI 10.1029/JC091iC09p10759 Jones EP, 2003, J GEOPHYS RES-OCEANS, V108, DOI 10.1029/2001JC001141 Jones EP, 2008, J GEOPHYS RES-OCEANS, V113, DOI 10.1029/2007JC004124 Jones EP, 1998, GEOPHYS RES LETT, V25, P765, DOI 10.1029/98GL00464 Karcher MJ, 2002, J GEOPHYS RES-OCEANS, V107, DOI 10.1029/2000JC000530 Karstensen J., 2005, Journal of Geophsical Research-Part C-Oceans, V110, DOI 10.1029/2004JC002510 Karstensen J., 2006, OMP OPTIMUM MULTIPAR Keeling RF, 2008, ATMOSPHERIC CO2 RECO KROUSE HR, 1971, CAN J EARTH SCI, V8, P1107 Leffanue H, 2004, J MARINE SYST, V48, P3, DOI 10.1016/j.jmarsys.2003.07.004 LEHMANN M, 1991, J GLACIOL, V37, P23 Lewis E., 1998, ORNLCDIAC105 US DEP Macdonald R. W., 2006, HDB ENV CHEM, P91 Macdonald RW, 2002, DEEP-SEA RES PT I, V49, P1769, DOI 10.1016/S0967-0637(02)00097-3 Macdonald RW, 1999, GEOPHYS RES LETT, V26, P2223, DOI 10.1029/1999GL900508 MACDONALD RW, 1995, J GEOPHYS RES-OCEANS, V100, P895, DOI 10.1029/94JC02700 MACDONALD RW, 1989, J GEOPHYS RES-OCEANS, V94, P18057, DOI 10.1029/JC094iC12p18057 Macdonald RW, 1999, MAR CHEM, V65, P3, DOI 10.1016/S0304-4203(99)00007-9 MACDONALD RW, 1987, J GEOPHYS RES-OCEANS, V92, P2939, DOI 10.1029/JC092iC03p02939 MACKAS DL, 1987, J GEOPHYS RES-OCEANS, V92, P2907, DOI 10.1029/JC092iC03p02907 Mathis JT, 2007, J GEOPHYS RES-OCEANS, V112, DOI 10.1029/2006JC003899 McGuire AD, 2009, ECOL MONOGR, V79, P523, DOI 10.1890/08-2025.1 McLaughlin FA, 2004, DEEP-SEA RES PT I, V51, P107, DOI 10.1016/j.dsr.2003.09.010 McLaughlin FA, 1996, J GEOPHYS RES-OCEANS, V101, P1183, DOI 10.1029/95JC02634 MEHRBACH C, 1973, LIMNOL OCEANOGR, V18, P897 MELLING H, 1993, CONT SHELF RES, V13, P1123, DOI 10.1016/0278-4343(93)90045-Y MELLING H, 1995, CONT SHELF RES, V15, P89, DOI 10.1016/0278-4343(94)P1814-R Miller LA, 2011, J GEOPHYS RES-OCEANS, V116, DOI 10.1029/2009JC006058 MILLERO FJ, 1993, MAR CHEM, V44, P143, DOI 10.1016/0304-4203(93)90199-X Millot R, 2003, GEOCHIM COSMOCHIM AC, V67, P1305, DOI 10.1016/S0016-7037(02)01207-3 Mucci A, 2010, J GEOPHYS RES-OCEANS, V115, DOI 10.1029/2009JC005330 Mundy CJ, 2009, GEOPHYS RES LETT, V36, DOI 10.1029/2009GL038837 Newton R, 2008, J GEOPHYS RES-OCEANS, V113, DOI 10.1029/2007JC004111 Nilsen F, 2008, CONT SHELF RES, V28, P1838, DOI 10.1016/j.csr.2008.04.015 Nomura D, 2006, TELLUS B, V58, P418, DOI 10.1111/j.1600-0889.2006.00204.x OSTLUND HG, 1984, J GEOPHYS RES-OCEANS, V89, P6373, DOI 10.1029/JC089iC04p06373 Overpeck J., 2005, EOS, V86, P312, DOI DOI 10.1029/2005EO340001 Overpeck JT, 2005, EOS, V86, P309, DOI [10.1029/2005EO340001, DOI 10.1029/2005E0340001, DOI 10.1029/2005EO340001] Papadimitriou S, 2004, GEOCHIM COSMOCHIM AC, V68, P1749, DOI 10.1016/j.gca.2003.07.004 Pickart RS, 2004, J GEOPHYS RES-OCEANS, V109, DOI 10.1029/2003JC001912 Pickart RS, 2009, J GEOPHYS RES-OCEANS, V114, DOI 10.1029/2008JC005009 Pipko II, 2002, PROG OCEANOGR, V55, P77, DOI 10.1016/S0079-6611(02)00071-X Retamal L, 2008, POLAR BIOL, V31, P363, DOI 10.1007/s00300-007-0365-0 ROBERTBALDO GL, 1985, ANAL CHEM, V57, P2564, DOI 10.1021/ac00290a030 Rudels B, 1996, J GEOPHYS RES-OCEANS, V101, P8807, DOI 10.1029/96JC00143 Rudels B, 2004, POLAR RES, V23, P181, DOI 10.1111/j.1751-8369.2004.tb00007.x Rysgaard S, 2007, J GEOPHYS RES-OCEANS, V112, DOI 10.1029/2006JC003572 Schlitzer R., 2009, OCEAN DATA VIEW Schlosser P, 2002, GEOPHYS RES LETT, V29, DOI 10.1029/2001GL013135 Semiletov IP, 2007, J MARINE SYST, V66, P204, DOI 10.1016/j.jmarsys.2006.05.012 Serreze MC, 2006, J GEOPHYS RES-OCEANS, V111, DOI 10.1029/2005JC003424 Serreze MC, 2007, SCIENCE, V315, P1533, DOI 10.1126/science.1139426 Shadwick E. H., 2009, BIOGEOSCI DISCUSS, V6, P971, DOI [10.5194/bgd-6-971-2009, DOI 10.5194/BGD-6-971-2009] Shadwick EH, 2011, LIMNOL OCEANOGR, V56, P303, DOI 10.4319/lo.2011.56.1.0303 Shadwick EH, 2011, CONT SHELF RES, V31, P806, DOI 10.1016/j.csr.2011.01.014 Shaw WJ, 2009, J GEOPHYS RES-OCEANS, V114, DOI 10.1029/2008JC004991 Shcherbina AY, 2003, SCIENCE, V302, P1952, DOI 10.1126/science.1088692 Sherr BF, 2003, DEEP-SEA RES PT I, V50, P529, DOI 10.1016/S0967-0637(03)00030-X Shimada K, 2006, GEOPHYS RES LETT, V33, DOI 10.1029/2005GL025624 Skogseth R, 2008, J GEOPHYS RES-OCEANS, V113, DOI 10.1029/2007JC004452 Spall MA, 2008, J PHYS OCEANOGR, V38, P1644, DOI 10.1175/2007JPO3829.1 Stroeve JC, 2005, GEOPHYS RES LETT, V32, DOI 10.1029/2004GL021810 Symon C., 2005, ARCTIC CLIMATE IMPAC Taylor JR, 2003, J GEOPHYS RES-OCEANS, V108, DOI 10.1029/2002JC001635 Telang S. A., 1991, BIOGEOCHEMISTRY MAJO, P75 Thomas H, 2011, J GEOPHYS RES-OCEANS, V116, DOI 10.1029/2011JC007120 Timmermans ML, 2008, J PHYS OCEANOGR, V38, P133, DOI 10.1175/2007JPO3782.1 TOMCZAK M, 1989, J GEOPHYS RES-OCEANS, V94, P16141, DOI 10.1029/JC094iC11p16141 Tremblay JE, 2008, J GEOPHYS RES-OCEANS, V113, DOI 10.1029/2007JC004547 Vallieres C, 2008, J MARINE SYST, V74, P756, DOI 10.1016/j.jmarsys.2007.12.002 White D, 2007, J GEOPHYS RES-BIOGEO, V112, DOI 10.1029/2006JG000353 Williams WJ, 2006, CONT SHELF RES, V26, P2352, DOI 10.1016/j.csr.2006.06.012 Williams WJ, 2008, J GEOPHYS RES-OCEANS, V113, DOI 10.1029/2006JC003591 Williams WJ, 2008, J MAR RES, V66, P645 Woodgate RA, 2006, GEOPHYS RES LETT, V33, DOI 10.1029/2006GL026931 Yamamoto-Kawai M, 2008, J GEOPHYS RES-OCEANS, V113, DOI 10.1029/2006JC003858 Yamamoto-Kawai M, 2009, J GEOPHYS RES-OCEANS, V114, DOI 10.1029/2008JC005000 Yamamoto-Kawai M, 2005, J GEOPHYS RES-OCEANS, V110, DOI 10.1029/2004JC002793 Yi Y, 2010, J HYDROL, V383, P223, DOI 10.1016/j.jhydrol.2009.12.038 Lansard, Bruno Mucci, Alfonso Miller, Lisa A. Macdonald, Robie W. Gratton, Yves Macdonald, Robie/A-7896-2012 Macdonald, Robie/0000-0002-1141-8520 CCGS Amundsen; CASES (Canadian Arctic Shelf Exchange Study) NSERC network (Natural Sciences and Engineering Research Council of Canada); Canadian Fund for Innovation; Canadian Coast Guard; Department of Fisheries and Oceans Canada; NSERC Discovery We thank the officers and crew of the CCGS Amundsen for their support and dedication to the CASES expedition. We are indebted to Constance Guignard, Nes Sutherland, Pascale Collin, Simon Belanger, Jens Ehn, Mike Arychuk and Owen Owens for their care and perseverance in collecting and analyzing the TA, TIC and pH samples at sea. Thanks must go to the CTD data acquisition group for these basic but critical measurements and the calibration of the various probes. Most of the plots and maps in this study were created with the ODV Software [Schlitzer, 2009]. We also thank A. Proshutinsky and two anonymous reviewers who provided constructive comments that helped to improve our manuscript. This study was funded through the CASES (Canadian Arctic Shelf Exchange Study) NSERC network (Natural Sciences and Engineering Research Council of Canada) and a Canadian Fund for Innovation grant to support the upgrade and operation of the CCGS Amundsen. Additional financial contributions were provided by the Canadian Coast Guard, the Strategic Science Fund of the Department of Fisheries and Oceans Canada, and NSERC Discovery grants to A. Mucci and Y. Gratton. 10 AMER GEOPHYSICAL UNION WASHINGTON J GEOPHYS RES-OCEANSWe examined the seasonal variability of water mass distributions in the southeastern Beaufort Sea from data collected between September 2003 and August 2004. Salinity, total alkalinity (TA) and isotopic composition (delta O-18) of seawater were used together as tracers of freshwater input, i.e., meteoric water and sea ice meltwater. We used an optimum multiparameter analysis to identify the different water masses, including the Mackenzie River, sea ice melt (SIM), winter polar mixed layer (PML), upper halocline water (UHW) with core salinity of 33.1 psu (Pacific origin) and Atlantic Water. Computed values of CO2 fugacity in seawater (fCO(2)-sw) show that the surface mixed layer (SML) remains mostly undersaturated (328 +/- 55 mu atm, n = 552) with respect to the average atmospheric CO2 concentration (380 +/- 5 mu atm) over the study period. The influence of the Mackenzie River (fCO(2-SW) > 500 mu atm) was relatively small in the southeastern Beaufort Sea, and significant fractions were only observed on the inner Mackenzie Shelf. The contribution of sea ice melt (fCO(2-SW) 600 mu atm) was usually located between 120 and 180 m depth, but could contribute to the SML during wind-driven upwelling events, in summer and autumn, and during brine-driven eddies, in winter

Socio-demographic and clinical characterization of patients with obsessive-compulsive tic-related disorder (OCTD) : An Italian multicenter study

© Copyright by Pacini Editore SrlIn the DSM-5 a new "tic-related" specifier for obsessive compulsive disorder (OCD) has been introduced, highlighting the importance of an accurate characterization of patients suffering from obsessive-compulsive tic-related disorder ("OCTD"). In order to characterize OCTD from a socio-demographic and clinical perspective, the present multicenter study was carried out. The sample consists of 266 patients, divided in two groups with lifetime diagnoses of OCD and OCTD, respectively. OCTD vs OCD patients showed a significant male prevalence (68.5% vs 48.5%; p < .001), a higher rate of psychiatric comorbidities (69.4 vs 50%; p < .001) - mainly with neurodevelopmental disorders (24 vs 0%; p < .001), a lower education level and professional status (middle school diploma: 25 vs 7.6%; full-Time job 44.4 vs 58%; p < .001). Moreover, OCTD vs OCD patients showed significantly earlier age of OCD and psychiatric comorbidity onsets (16.1 ± 10.8 vs 22.1 ± 9.5 years; p < .001, and 18.3 ± 12.8 vs 25.6 ± 9.4: p < .001, respectively). Patients with OCTD patients were treated mainly with antipsychotic and with a low rate of benzodiazepine (74.2 vs 38.2% and 20.2 vs 31.3%, respectively; p < .001). Finally, OCTD vs OCD patients showed higher rates of partial treatment response (58.1 vs 38%; p < .001), lower rates of current remission (35.5 vs 54.8%; p < .001) and higher rates of suicidal ideation (63.2 vs 41.7%; p < .001) and attempts (28.9 vs 8.3%; p < .001). Patients with OCTD report several unfavorable socio-demographic and clinical characteristics compared to OCD patients without a history of tic. Additional studies on larger sample are needed to further characterize OCTD patients from clinical and therapeutic perspectives.Peer reviewedFinal Published versio

Mediterranean Diet Score and prostate cancer risk in a Swedish population-based case–control study

Several individual components of the Mediterranean diet have been shown to offer protection against prostate cancer. The present study is the first to investigate the association between adherence to the Mediterranean diet and the relative risk of prostate cancer. We also explored the usefulness of the Mediterranean Diet Score (MDS) in a non-Mediterranean population. FFQ data were obtained from 1482 incident prostate cancer patients and 1108 population-based controls in the Cancer of the Prostate in Sweden (CAPS) study. We defined five MDS variants with different components or using either study-specific intakes or intakes in a Greek reference population as cut-off values between low and high intake of each component. Unconditional logistic regression was used to estimate the relative risk of prostate cancer for high and medium v. low MDS, as well as potential associations with the individual score components. No statistically significant association was found between adherence to the Mediterranean diet based on any of the MDS variants and prostate cancer risk (OR range: 0·96–1·19 for total prostate cancer, comparing high with low adherence). Overall, we found little support for an association between the Mediterranean diet and prostate cancer in this Northern European study population. Despite potential limitations inherent in the study or in the build-up of a dietary score, we suggest that the original MDS with study-specific median intakes as cut-off values between low and high intake is useful in assessing the adherence to the Mediterranean diet in non-Mediterranean populations

Radiographers supporting radiologists in the interpretation of screening mammography: a viable strategy to meet the shortage in the number of radiologists.

BackgroundAn alternative approach to the traditional model of radiologists interpreting screening mammography is necessary due to the shortage of radiologists to interpret screening mammograms in many countries.MethodsWe evaluated the performance of 15 Mexican radiographers, also known as radiologic technologists, in the interpretation of screening mammography after a 6 months training period in a screening setting. Fifteen radiographers received 6 months standardized training with radiologists in the interpretation of screening mammography using the Breast Imaging Reporting and Data System (BI-RADS) system. A challenging test set of 110 cases developed by the Breast Cancer Surveillance Consortium was used to evaluate their performance. We estimated sensitivity, specificity, false positive rates, likelihood ratio of a positive test (LR+) and the area under the subject-specific Receiver Operating Characteristic (ROC) curve (AUC) for diagnostic accuracy. A mathematical model simulating the consequences in costs and performance of two hypothetical scenarios compared to the status quo in which a radiologist reads all screening mammograms was also performed.ResultsRadiographer's sensitivity was comparable to the sensitivity scores achieved by U.S. radiologists who took the test but their false-positive rate was higher. Median sensitivity was 73.3 % (Interquartile range, IQR: 46.7-86.7 %) and the median false positive rate was 49.5 % (IQR: 34.7-57.9 %). The median LR+ was 1.4 (IQR: 1.3-1.7 %) and the median AUC was 0.6 (IQR: 0.6-0.7). A scenario in which a radiographer reads all mammograms first, and a radiologist reads only those that were difficult for the radiographer, was more cost-effective than a scenario in which either the radiographer or radiologist reads all mammograms.ConclusionsGiven the comparable sensitivity achieved by Mexican radiographers and U.S. radiologists on a test set, screening mammography interpretation by radiographers appears to be a possible adjunct to radiologists in countries with shortages of radiologists. Further studies are required to assess the effectiveness of different training programs in order to obtain acceptable screening accuracy, as well as the best approaches for the use of non-physician readers to interpret screening mammography

Early Life Residence, Fish Consumption, and Risk of Breast Cancer.

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/Open To access publisher's full text version of this article click on the hyperlink at the bottom of the pageBackground: Little is known about fish intake throughout the life course and the risk of breast cancer.Methods: We used data on the first residence of 9,340 women born 1908 to 1935 in the Reykjavik Study as well as food frequency data for different periods of life from a subgroup of the cohort entering the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (n = 2,882).Results: During a mean follow-up of 27.3 years, 744 women were diagnosed with breast cancer in the Reykjavik Study. An inverse association of breast cancer was observed among women who lived through the puberty period in coastal villages, compared with women residing in the capital area [HR, 0.78; 95% confidence interval (CI), 0.61-0.99]. In the subgroup analysis of this Icelandic population, generally characterized by high fish intake, we found an indication of lower risk of breast cancer among women with high fish consumption (more than 4 portions per week) in adolescence (HR, 0.71; 95% CI, 0.44-1.13) and midlife (HR, 0.46; 95% CI, 0.22-0.97), compared with low consumers (2 portions per week or less). No association was found for fish liver oil consumption in any time period, which could be due to lack of a reference group with low omega-3 fatty acids intake in the study group.Conclusions: Our findings suggest that very high fish consumption in early to midlife may be associated with a reduced risk of breast cancer.Impact: Very high fish consumption in early adulthood to midlife may be associated with decreased risk of breast cancer. Cancer Epidemiol Biomarkers Prev; 26(3); 346-54. ©2016 AACR.NIH Intramural Research Program of the National Institute on Aging Icelandic Heart Association Icelandic Parliament Icelandic Centre for Research, RANNIS Public Health Fund of the Icelandic Directorate of Healt

The Heritability of Prostate Cancer in the Nordic Twin Study of Cancer

BACKGROUND: Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age. METHODS: To address this question, we undertook the world's largest prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic and 30,054 dizygotic same sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability. RESULTS: The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability (heritability=58% (95% CI 52%–63%) of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary. CONCLUSIONS: Results from the population based twin cohort, indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age IMPACT: Findings impact the search for genetic and epigenetic markers and frame prevention efforts

Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease

Background Prostate cancer (PrCa) demonstrates a heterogeneous clinical presentation ranging from largely indolent to lethal. We sought to identify a signature of rare inherited variants that distinguishes between these two extreme phenotypes. Methods We sequenced germline whole exomes from 139 aggressive (metastatic, age of diagnosis < 60) and 141 non-aggressive (low clinical grade, age of diagnosis ≥60) PrCa cases. We conducted rare variant association analyses at gene and gene set levels using SKAT and Bayesian risk index techniques. GO term enrichment analysis was performed for genes with the highest differential burden of rare disruptive variants. Results Protein truncating variants (PTVs) in specific DNA repair genes were significantly overrepresented among patients with the aggressive phenotype, with BRCA2, ATM and NBN the most frequently mutated genes. Differential burden of rare variants was identified between metastatic and non-aggressive cases for several genes implicated in angiogenesis, conferring both deleterious and protective effects. Conclusions Inherited PTVs in several DNA repair genes distinguish aggressive from non-aggressive PrCa cases. Furthermore, inherited variants in genes with roles in angiogenesis may be potential predictors for risk of metastases. If validated in a larger dataset, these findings have potential for future clinical application