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Emanuelsson, Monica
Publications (9 of 9) Show all publications
Bailey-Wilson, J. E., Childs, E. J., Cropp, C. D., Schaid, D. J., Xu, J., Camp, N. J., . . . Isaacs, W. B. (2012). Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families. BMC Medical Genetics, 13, 46
Open this publication in new window or tab >>Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families
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2012 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, p. 46-Article in journal (Refereed) Published
Abstract [en]

Background: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.

Methods: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.

Results: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.

Conclusions: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.

Place, publisher, year, edition, pages
London: BioMed Central, 2012
National Category
Genetics
Identifiers
urn:nbn:se:umu:diva-62806 (URN)10.1186/1471-2350-13-46 (DOI)000311143100001 ()
Available from: 2013-01-02 Created: 2012-12-18 Last updated: 2018-06-08Bibliographically approved
Lu, L., Cancel-Tassin, G., Valeri, A., Cussenot, O., Lange, E. M., Cooney, K. A., . . . Isaacs, W. B. (2012). Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG. The Prostate, 72(4), 410-426
Open this publication in new window or tab >>Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG
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2012 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 72, no 4, p. 410-426Article in journal (Refereed) Published
Abstract [en]

BACKGROUND In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD?=?1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. METHODS. In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. RESULTS. Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD cores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. CONCLUSIONS. These results will be useful in prioritizing future susceptibility gene discovery efforts in thiscommon cancer. Prostate 72: 410-426, 2012. (C) 2011 Wiley Periodicals, Inc.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-52366 (URN)10.1002/pros.21443 (DOI)000299159000007 ()21748754 (PubMedID)
Available from: 2012-02-20 Created: 2012-02-20 Last updated: 2018-06-08Bibliographically approved
Jin, G., Lu, L., Cooney, K. A., Ray, A. M., Zuhlke, K. A., Lange, E. M., . . . Xu, J. (2012). Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG). Human Genetics, 131(7), 1095-1103
Open this publication in new window or tab >>Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG)
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2012 (English)In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 131, no 7, p. 1095-1103Article in journal (Refereed) Published
Abstract [en]

Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case-control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case-control GWAS are also associated with disease risk in HPC families.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-52482 (URN)10.1007/s00439-011-1136-0 (DOI)000305195400008 ()22198737 (PubMedID)
Available from: 2012-02-22 Created: 2012-02-22 Last updated: 2018-06-08Bibliographically approved
Christensen, G. B., Baffoe-Bonnie, A. B., George, A., Powell, I., Bailey-Wilson, J. E., Carpten, J. D., . . . Camp, N. J. (2010). Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses.. The Prostate, 70, 735-744
Open this publication in new window or tab >>Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses.
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2010 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, p. 735-744Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS: We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS: Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS: Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate (c) 2010 Wiley-Liss, Inc.

Keywords
genetic epidemiology, meta analysis, susceptibility, predisposition, cancer
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-33180 (URN)10.1002/pros.21106 (DOI)000277338800006 ()20333727 (PubMedID)
Available from: 2010-04-14 Created: 2010-04-14 Last updated: 2018-06-08Bibliographically approved
Bergman, A., Sahlin, P., Emanuelsson, M., Carén, H., Tarnow, P., Martinsson, T., . . . Stenman, G. (2009). Germline mutation screening of the Saethre-Chotzen-associated genes TWIST1 and FGFR3 in families with BRCA1/2-negative breast cancer.. Scandinavian journal of plastic and reconstructive surgery and hand surgery / Nordisk plastikkirurgisk forening [and] Nordisk klubb for handkirurgi, 43(5), 251-255
Open this publication in new window or tab >>Germline mutation screening of the Saethre-Chotzen-associated genes TWIST1 and FGFR3 in families with BRCA1/2-negative breast cancer.
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2009 (English)In: Scandinavian journal of plastic and reconstructive surgery and hand surgery / Nordisk plastikkirurgisk forening [and] Nordisk klubb for handkirurgi, ISSN 1651-2073, Vol. 43, no 5, p. 251-255Article in journal (Refereed) Published
Abstract [en]

Saethre-Chotzen syndrome is one of the most common craniosynostosis syndromes. It is an autosomal dominantly inherited disorder with variable expression that is caused by germline mutations in the TWIST1 gene or more rarely in the FGFR2 or FGFR3 genes. We have previously reported that patients with Saethre-Chotzen syndrome have an increased risk of developing breast cancer. Here we have analysed a cohort of 26 women with BRCA1/2-negative hereditary breast cancer to study whether a proportion of these families might have mutations in Saethre-Chotzen-associated genes. DNA sequence analysis of TWIST1 showed no pathogenic mutations in the coding sequence in any of the 26 patients. MLPA (multiplex ligation-dependent probe amplification)-analysis also showed no alterations in copy numbers in any of the craniofacial disorder genes MSX2, ALX4, RUNX2, EFNB1, TWIST1, FGFR1, FGFR2,FGFR3, or FGFR4. Taken together, our findings indicate that mutations in Saethre-Chotzen-associated genes are uncommon or absent in BRCA1/2-negative patients with hereditary breast cancer.

Identifiers
urn:nbn:se:umu:diva-27712 (URN)19863427 (PubMedID)
Available from: 2009-11-17 Created: 2009-11-17 Last updated: 2018-06-08
Camp, N. J., Cannon-Albright, L. A., Farnham, J. M., Baffoe-Bonnie, A. B., George, A., Powell, I., . . . Isaacs, W. B. (2007). Compelling evidence for a prostate cancer gene at 22q12.3 by the International Consortium for Prostate Cancer Genetics.. Hum Mol Genet, 16(11), 1271-1278
Open this publication in new window or tab >>Compelling evidence for a prostate cancer gene at 22q12.3 by the International Consortium for Prostate Cancer Genetics.
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2007 (English)In: Hum Mol Genet, ISSN 0964-6906, Vol. 16, no 11, p. 1271-1278Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-14246 (URN)doi:10.1093/hmg/ddm075 (DOI)17478474 (PubMedID)
Available from: 2007-05-25 Created: 2007-05-25 Last updated: 2018-06-09Bibliographically approved
Sahlin, P., Windh, P., Lauritzen, C., Emanuelsson, M., Grönberg, H. & Stenman, G. (2007). Women with Saethre-Chotzen syndrome are at increased risk of breast cancer.. Genes Chromosomes Cancer, 46(7), 656-660
Open this publication in new window or tab >>Women with Saethre-Chotzen syndrome are at increased risk of breast cancer.
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2007 (English)In: Genes Chromosomes Cancer, ISSN 1045-2257, Vol. 46, no 7, p. 656-660Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-13461 (URN)doi:10.1002/gcc.20449 (DOI)17437280 (PubMedID)
Available from: 2008-01-12 Created: 2008-01-12 Last updated: 2018-06-09Bibliographically approved
Cederquist, K., Emanuelsson, M., Göransson, I., Holinski-Feder, E., Müller-Koch, Y., Golovleva, I. & Grönberg, H. (2004). Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden. International Journal of Cancer, 109(3), 370-376
Open this publication in new window or tab >>Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: a population-based study in northern Sweden
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2004 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 109, no 3, p. 370-376Article in journal (Refereed) Published
Abstract [en]

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that predisposes to predominantly colorectal and endometrial cancers due to germline mutations in DNA mismatch repair genes, mainly MLH1, MSH2 and in families with excess endometrial cancer also MSH6. In this population-based study, we analysed the mutation spectrum of the MLH1, MSH2 and MSH6 genes in a cohort of patients with microsatellite unstable double primary tumours of the colorectum and the endometrium by PCR, DHPLC and sequencing. Fourteen of the 23 patients (61%) had sequence variants in MLH1, MSH2 or MSH6 that likely affect the protein function. A majority (10/14) of the mutations was found among probands diagnosed before age 50. Five of the mutations (36%) were located in MLH1, 3 (21%) in MSH2 and 6 (43%) in MSH6. MSH6 seem to have larger impact in our population than in other populations, due to a founder effect since all of the MSH6 families originate from the same geographical area. MSH6 mutation carriers have later age of onset of both colorectal cancer (62 vs. 51 years) and endometrial cancer (58 vs. 48 years) and a larger proportion of endometrial cancer than MLH1 or MSH2 mutation carriers. We can conclude that patients with microsatellite unstable double primary cancers of the colorectum and the endometrium have a very high risk of carrying a mutation not only in MLH1 or MSH2 but also in MSH6, especially if they get their first cancer diagnosis before the age of 50. Copyright 2004 Wiley-Liss, Inc.

Keywords
HNPCC, DHPLC, double primary tumours, colorectal cancer, endometrial cancer, population based, mismatch repair genes
Identifiers
urn:nbn:se:umu:diva-15020 (URN)10.1002/ijc.11718 (DOI)14961575 (PubMedID)
Available from: 2007-09-13 Created: 2007-09-13 Last updated: 2018-06-09Bibliographically approved
Wiklund, F., Emanuelsson, M., Stenman, E., Gillanders, E., Trent, J. & Grönberg, H. Comprehensive evaluation of malignancies associated with hereditary prostate cancer: confirmation of a common genetic basis for prostate and gastric cancer and suggestive linkage to Xp21.
Open this publication in new window or tab >>Comprehensive evaluation of malignancies associated with hereditary prostate cancer: confirmation of a common genetic basis for prostate and gastric cancer and suggestive linkage to Xp21
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-4013 (URN)
Available from: 2004-05-13 Created: 2004-05-13 Last updated: 2018-06-09Bibliographically approved
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