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PDF file - 99K, LocusZoom plots of the top two loci using stage 1 P values.

Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer.Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb).Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03–1.16] for the A/G genotype and 1.17 (95% CI, 1.05–1.30) for the G/G genotype (P = 1.6 × 10−4 in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P = 2.4 × 10−5).Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus.Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev; 21(6); 980–7. ©2012 AACR.

PDF file, 112KB.

PDF file - 70K, Candidate inflammation genes selected for stage 1 study, Annotation of potentially functional SNPs in linkage disequilibrium (r2 > 0.2) with rs352038 (CXCL3) or rs3918249 (MMP9)

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Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls.Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85–0.99); CXCL3, 1.16 (1.05–1.29); IL6, 1.08 (1.00–1.17); MSR1, 0.90 (0.82–0.98); and MMP9, 0.91 (0.87–0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer.Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(2); 216–23. ©2012 AACR.

PDF file, 123KB, Detailed Description of the Case and Control Sample Sets.

Bloom's syndrome is a rare autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia, including breast cancer. Whether monoallelic BLM mutations predispose to breast cancer has been a long-standing question. A nonsense mutation, p.Q548X, has recently been associated with an increased risk for breast cancer in a Russian case-control study. In the present work, we have investigated the prevalence of this Slavic BLM founder mutation in a total of 3,188 breast cancer cases and 2,458 controls from Bashkortostan, Belarus, Ukraine, and Kazakhstan. The p.Q548X allele was most frequent in Russian patients (0.8 %) but was also prevalent in Byelorussian and Ukrainian patients (0.5 and 0.6 %, respectively), whereas it was absent in Altaic or other non-European subpopulations. In a combined analysis of our four case-control series, the p.Q548X mutation was significantly associated with breast cancer (Mantel-Haenszel OR 5.1, 95 % CI 1.2; 21.9, p = 0.03). A meta-analysis with the previous study from the St. Petersburg area corroborates the association (OR 5.7, 95 % CI 2.0; 15.9, p = 3.7 × 10(-4)). A meta-analysis for all published truncating mutations further supports the association of BLM with breast cancer, with an estimated two- to five-fold increase in risk (OR 3.3, 95 %CI 1.9; 5.6, p = 1.9 × 10(-5)). Altogether, these data indicate that BLM is not only a gene for Bloom's syndrome but also might represent a breast cancer susceptibility gene.

Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls. Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85–0.99); CXCL3, 1.16 (1.05–1.29); IL6, 1.08 (1.00–1.17); MSR1, 0.90 (0.82–0.98); and MMP9, 0.91 (0.87–0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(2); 216–23. ©2012 AACR.

Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer. Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb). Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03–1.16] for the A/G genotype and 1.17 (95% CI, 1.05–1.30) for the G/G genotype (P = 1.6 × 10−4 in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P = 2.4 × 10−5). Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus. Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev; 21(6); 980–7. ©2012 AACR.

Background and objectives Prostate cancer has a genetic component, and single nucleotide polymorphisms (SNPs) can contribute to the risk. We aimed to investigate the role of polymorphisms in 10 candidate genes with a key function in apoptosis. Methods and materials Eight coding SNPs were chosen in ATM (Ser49Cys), BID (Ser56Cys), CASP8 (Asp302His), CASP10 (Val410Ile), LGALS3 (Pro64His), RASSF1 (Ser133Ala), TP53 (Arg72Pro), and TP53AIP1 (Ala7Val), and two non-coding SNPs were selected in BCL2 (-938C/A) and HDM2 (SNP309). A hospital-based case-control series of 510 prostate cancer patients and 490 healthy males from Northern Germany were genotyped for these polymorphisms. Results SNP rs4644 in LGALS3 showed evidence for a protective effect of the minor allele, encoding the His64 variant (OR 0.82, 95% CI 0.69;0.99, P = 0.04). Carriers were underrepresented among cases under a dominant model (OR 0.71; 95% CI 0.54;0.92; P = 0.01), and the effect appeared more pronounced in patients diagnosed before the age of 60 years (OR 0.52; 95% CI 0.31;0.85, P = 0.01). The other nine polymorphisms did not vary significantly between cases and controls, though subtle trends were noted for BCL2 (P = 0.07) and CASP10 (P = 0.08). The Asp302His variant of CASP8 tended to associate with a protective effect in the group with higher Gleason score under a dominant model (P = 0.03). Carriers of either the CASP8 or the CASP10 variants were underrepresented in the prostate cancer series (P = 0.02). Conclusions These results provide first evidence to implicate the functional Pro64His variant of galectin-3 (LGALS3) in the genetic susceptibility towards prostate cancer. The potential role of polymorphisms in BCL2, CASP8, and CASP10 merits further investigation.

Acute aortic dissection is a life-threatening disease with a high rate of mortality. The dissection of the artery with a distal blood flow can explain the variable and changeable symptoms. Aortic dissections require immediate diagnosis and therapy.In the Institute of Legal Medicine of the Hannover Medical School, 34 cases of aortic dissection were found during autopsy between 2006 and 2009. The cases were analysed retrospectively.In the majority of cases (55.9%) an antemortem medical consultation has taken place. In only one case an aortic dissection could be diagnosed at a later time.Key in the management of acute aortic dissection is to maintain a high clinical index of suspicion for this diagnosis. Etiologically hereditary diseases (Marfan syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome) should be taken into consideration as a possible cause. In all unexpected deaths of young adults an autopsy should be performed to detect the cause of death and for genetic testing to provide information for the relatives in case an aortic aneurysm can be found.

Hintergrund und Fragestellung: Myokardinfarkte gehören trotz verbesserter Diagnosemaßnahmen auch heute noch zu den am häufigsten fehldiagnostizierten Erkrankungen. Dies gilt insbesondere für Patienten mit atypischen oder fehlenden Symptomen. Nicht erkannte Myokardinfarkte verursachen einen Großteil der durch ärztliche Kunstfehler hervorgerufenen Schäden. Ziel dieser Untersuchung war es, die Akten der an einem Herzinfarkt gestorbenen Patienten auszuwerten und im Hinblick auf ein vorwerfbares fehlerhaftes ärztliches Verhalten bei Nichterkennen eines Herzinfarkts in einer kurz vor dem Tod erfolgten ärztlichen Konsultation zu analysieren. Methoden: Im Institut für Rechtsmedizin der Medizinischen Hochschule Hannover wurden in den Jahren 2008 und 2009 109 Patienten obduziert, die an einem Herzinfarkt gestorben waren. Die Akten der Patienten wurden retrospektiv ausgewertet und auf kurz vor dem Tod erfolgte Arztkonsultationen, angegebene Symptome und Diagnosemaßnahmen analysiert. Ergebnisse: 38 Personen (34,9 %) hatten unmittelbar vor ihrem Tod einen Arzt aufgesucht oder waren im Krankenhaus gestorben. In 5 Fällen konnte die Verdachtsdiagnose eines Herzinfarktes gestellt werden. Bei den übrigen 33 Patienten wurde der Myokardinfarkt nicht erkannt. In 2 Fällen wurde zur Beurteilung eines etwaigen ärztlichen Fehlverhaltens eine zusätzliche kardiologische Fachbegutachtung empfohlen und bei 2 weiteren Fällen wurde bei unzureichender diagnostischer Abklärung bereits von Seiten der Rechtsmedizin ein Vorwurf wegen ärztlichen Fehlverhaltens erhoben. Schlussfolgerung: Eine Obduktion ist die zuverlässigste Methode zur Beweissicherung, um Fehldiagnosen bzw. nicht erkannte Erkrankungen festzustellen. Andererseits kann eine Obduktion auch entlastende Indizien im ärztlichen Kunstfehlerprozess liefern.

Akute Aortendissektionen stellen eine lebensbedrohliche Erkrankung mit einer hohen Mortalitatsrate dar. Durch eine Spaltbildung der aortalen Wandschichten mit nach distal fortschreitender Wuhlblutung konnen eine Vielzahl von unterschiedlichen und wechselhaften Symptomen auftreten. Aortendissektionen erfordern eine unverzugliche Diagnosestellung und Therapie. Am Institut fur Rechtsmedizin der Medizinischen Hochschule Hannover wurden in den Jahren 2006 bis 2009 34 Verstorbene mit einem Aneurysma dissecans obduziert. Die Falle wurden retrospektiv analysiert. Die Mehrzahl der verstorbenen Personen (55,9%) hatte unmittelbar vor dem Tod einen Arzt aufgesucht. Nur in einem Fall konnte ein disseziierendes Aortenaneurysma verspatet diagnostiziert werden. Ein hohes Mas an klinischem Verdacht auf das Vorliegen einer Aortendissektion ist fur die richtige Diagnosefindung erforderlich. Ursachlich kommen auch hereditare Erkrankungen (Marfan-Syndrom, Ehlers- Danlos-Syndrom, Loeys-Dietz-Syndrom) in Betracht. Bei allen ungeklarten Todesfallen von jungen Erwachsenen sollte eine Obduktion durchgefuhrt werden, um die Todesursache zu klaren und im Falle einer vorliegenden Aortendissektion eine genetische Testung und Information der Familienmitglieder vornehmen zu konnen.