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PURPOSE: The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL.PARTICIPANTS AND METHODS: Among 520,000 healthy participants enrolled onto the EPIC (European Prospective Investigation Into Cancer and Nutrition) cohort, we identified 100 who developed FL 2 to 161 months after enrollment. Prediagnostic blood from these and 218 controls were screened for t(14;18) using sensitive polymerase chain reaction-based assays. Results were subsequently validated in an independent cohort (65 case participants; 128 controls). Clonal relationships between t(14;18) cells and FL were also assessed by molecular backtracking of paired prediagnostic blood and tumor samples.RESULTS: Clonal analysis of t(14;18) junctions in paired prediagnostic blood versus tumor samples demonstrated that progression to FL occurred from t(14;18)-positive committed precursors. Furthermore, healthy participants at enrollment who developed FL up to 15 years later showed a markedly higher t(14;18) prevalence and frequency than controls (P < .001). Altogether, we estimated a 23-fold higher risk of subsequent FL in blood samples associated with a frequency > 10(-4) (odds ratio, 23.17; 95% CI, 9.98 to 67.31; P < .001). Remarkably, risk estimates remained high and significant up to 15 years before diagnosis.CONCLUSION: High t(14;18) frequency in blood from healthy individuals defines the first predictive biomarker for FL, effective years before diagnosis.

BACKGROUND: Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status. METHODS: Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression. RESULTS: Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 x 10(-20) and 1.5 x 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 x 10(-4)). CONCLUSION: The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer. British Journal of Cancer (2012) 106, 389-396. doi:10.1038/bjc.2011.461 www.bjcancer.com Published online 1 November 2011 (C) 2012 Cancer Research UK

BACKGROUND: Recent studies have identified several single-nucleotide polymorphisms (SNPs) associated with the risk of breast cancer and parity and age at first childbirth are well established and important risk factors for breast cancer. The aim of the present study was to examine the interaction between these environmental factors and genetic variants on breast cancer risk. METHODS: The Malmö Diet and Cancer Study (MDCS) included 17 035 female participants, from which 728 incident breast cancer cases were matched to 1448 controls. The associations between 14 SNPs and breast cancer risk were investigated in different strata of parity and age at first childbirth. A logistic regression analysis for the per allele risk, adjusted for potential confounders yielded odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Six of the previously identified SNPs showed a statistically significant association with breast cancer risk: rs2981582 (FGFR2), rs3803662 (TNRC9), rs12443621 (TNRC9), rs889312 (MAP3K1), rs3817198 (LSP1) and rs2107425 (H19). We could not find any statistically significant interaction between the effects of tested SNPs and parity/age at first childbirth on breast cancer risk after adjusting for multiple comparisons. CONCLUSIONS: The results of this study are in agreement with previous studies of null interactions between tested SNPs and parity/age at first childbirth with regard to breast cancer risk.

BACKGROUND: Breast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT). METHODS: We analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case-control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model. RESULTS: One SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction = 0.03). There were no significant interactions after correction for multiple testing. CONCLUSIONS: We conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials.

Klinisk kemi i praktisk medicin används som kurslitteratur för läkare, biomedicinska analytiker och biomedicinare sedan 40 år tillbaka. Den finns på avdelningar, mottagningar och vårdcentraler - överallt där man behöver ta prover för kliniskt kemiska analyser och tolka deras resultat. Nu föreligger den i sin nionde upplaga efter omfattande revision och med nyskrivna kapitel. I denna upplaga har innehållet organiserats med tydlig anknytning till kliniska problemområden. Alla kapitel har grundligt reviderats. Avsnitten om tolkning av analysresultat, allergi och autoimmunitet, hjärtinfarkt och hjärtskademarkörer, digestionsorganens sjukdomar, graviditet, infertilitet och prenataldiagnostik samt läkemedel, förgiftningar och missbruk är helt nyskrivna. Boken kan användas både för att slå upp fakta om specifika analyser och för att förstå de sjukdomsmekanismer som är av betydelse för tolkningen av laboratorieresultat. Modern medicinsk praxis är patientcentrerad och har sitt fundament i ett nära samspel mellan klinik, laboratorier och patienter. Kunskapsfragment inom klinisk kemi är lättillgängliga för alla och envar på nätet, men ger sällan den helhetsbild som behövs för grundlig förståelse och därmed optimal användning av laboratorieanalyser. Denna bok ger sådan helhetsbild.

Background. Methylmalonic acid (MMA), a sensitive biomarker of functional vitamin B12 deficiency, is commonly determined by gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods using manual extraction and derivatization of MMA to reduce polarity prior to separation. Methods. In the present study we introduce a semi-automated extraction on a strong anion exchanger, HPLC separation on a BEH-amide column to separate serum MMA from its abundant isoform, succinic acid, followed by MS/MS detection and quantification. Results. The extraction of MMA plus internal standard provides full recovery and the method is linear between 0.03 mu mol/L and 20.0 mu mol/L (r(2) = 1.0) with intra-and inter-assay imprecision of 2.2%. Agreement with other laboratories has been demonstrated in external proficiency testing. Compared to both conventional GC-MS and LC-MS/MS methods, the correlation is r(2) > 0.99. Conclusions. The use of robotic pipetting, elimination of derivatization and improved separation by the BEH-amide column combined with HILIC chromatographic conditions significantly improve sample throughput compared to conventional methods. Using a single pipetting robot and LC-MS/MS instrument, this method is currently performing 180 analyses per day from 10 regional hospitals and several additional distant sites.

BACKGROUND AND PURPOSE: Extracellular adenosine triphosphate (ATP) regulates inflammatory cells by activation of the P2X(7) receptor. We hypothesized that polymorphisms in P2RX7 influence the risk of ischemic heart disease (IHD), ischemic stroke (IS) and cardiovascular risk factors and tested this hypothesis using genetic association studies. METHODS: Two loss-of-function SNPs in P2RX7 were genotyped in 1244 IHD cases and 2488 controls as well as 5969 individuals with cardiovascular risk factors. Eleven SNPs in a 250 kb region on chromosome 12 spanning P2RX7 as well as neighboring genes OASL, P2RX4 and CAMKK2 were genotyped in 4138 individuals with IS and 2528 controls. Association was examined using linear and logistic regression models with an additive genetic model. RESULTS: The common loss-of-function variant rs3751143 was significantly associated with a decreased risk of IHD in smokers (P = 0.03) as well as decreased risk of IS (OR 0.89; 95% CI = 0.81-0.97; P = 0.012). In addition, an intronic SNP in CAMKK2, rs2686342, were associated with a decreased risk of IS (OR 0.89; 95% CI = 0.82-0.97; P = 0.011). In subgroup analyses, both SNPs were associated with decreased risk of IS in individuals with hypertension (P = 0.045 and 0.015, respectively). CONCLUSIONS: A common loss-of-function missense variant in the gene encoding the P2X(7) receptor is associated with reduced risk of IS and with IHD in smokers. These findings might implicate a role of purinergic signaling in atherogenesis or atherothrombosis.