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19 results on '"Alexiusdottir, K."'

1. Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin

Author

Rafnar, T., Sigurjonsdottir, G.R., Stacey, S.N., Halldorsson, G., Sulem, P., Pardo, L.M., Helgason, H., Sigurdsson, S.T., Gudjonsson, T., Tryggvadottir, L., Olafsdottir, G.H., Jonasson, J.G., Alexiusdottir, K., Sigurdsson, A., Gudmundsson, J., Saemundsdottir, J., Sigurdsson, J.K., Johannsdottir, H., Uitterlinden, A., Vermeulen, S.H., Galesloot, T.E., Allain, D.C., Lacko, M., Sigurgeirsson, B., Thorisdottir, K., Johannsson, O.T., Sigurdsson, F., Ragnarsson, G.B., Isaksson, H., Hardardottir, H., Gudbjartsson, T., Gudbjartsson, D.F., Masson, G., Kiemeney, B., Toland, A.E., Nijsten, T., Peters, W.H.M., Olafsson, J.H., Jonsson, S., Thorsteinsdottir, U., Thorleifsson, G., Stefansson, K., Rafnar, T., Sigurjonsdottir, G.R., Stacey, S.N., Halldorsson, G., Sulem, P., Pardo, L.M., Helgason, H., Sigurdsson, S.T., Gudjonsson, T., Tryggvadottir, L., Olafsdottir, G.H., Jonasson, J.G., Alexiusdottir, K., Sigurdsson, A., Gudmundsson, J., Saemundsdottir, J., Sigurdsson, J.K., Johannsdottir, H., Uitterlinden, A., Vermeulen, S.H., Galesloot, T.E., Allain, D.C., Lacko, M., Sigurgeirsson, B., Thorisdottir, K., Johannsson, O.T., Sigurdsson, F., Ragnarsson, G.B., Isaksson, H., Hardardottir, H., Gudbjartsson, T., Gudbjartsson, D.F., Masson, G., Kiemeney, B., Toland, A.E., Nijsten, T., Peters, W.H.M., Olafsson, J.H., Jonsson, S., Thorsteinsdottir, U., Thorleifsson, G., and Stefansson, K.

Abstract

Contains fulltext : 195644.pdf (publisher's version ) (Closed access), Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.

Published
2018

2. Sequence variant at 4q25 near PITX2 associates with appendicitis

Author

Kristjansson, R.P., Benonisdottir, S., Oddsson, A., Galesloot, T.E., Thorleifsson, G., Aben, K.K.H., Davidsson, O.B., Jonsson, S., Arnadottir, G.A., Jensson, B.O., Walters, G.B., Sigurdsson, J.K., Sigurdsson, S., Holm, H., Arnar, D.O., Thorgeirsson, G., Alexiusdottir, K., Jonsdottir, I., Thorsteinsdottir, U., Kiemeney, L.A.L.M., Jonsson, T., Gudbjartsson, D.F., Rafnar, T., Sulem, P., Stefansson, K., Kristjansson, R.P., Benonisdottir, S., Oddsson, A., Galesloot, T.E., Thorleifsson, G., Aben, K.K.H., Davidsson, O.B., Jonsson, S., Arnadottir, G.A., Jensson, B.O., Walters, G.B., Sigurdsson, J.K., Sigurdsson, S., Holm, H., Arnar, D.O., Thorgeirsson, G., Alexiusdottir, K., Jonsdottir, I., Thorsteinsdottir, U., Kiemeney, L.A.L.M., Jonsson, T., Gudbjartsson, D.F., Rafnar, T., Sulem, P., and Stefansson, K.

Abstract

Contains fulltext : 174164.pdf (publisher's version ) (Open Access), Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 x 10-11). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.

Published
2017

3. Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer

Author

Rafnar, T., Sulem, P., Thorleifsson, G., Vermeulen, S., Helgason, H., Saemundsdottir, J., Gudjonsson, S.A., Sigurdsson, A., Stacey, S.N., Gudmundsson, J., Johannsdottir, H., Alexiusdottir, K., Petursdottir, V., Nikulasson, S., Geirsson, G., Jonsson, T., Aben, K.K.H., Grotenhuis, A.J., Verhaegh, G.W.C.T., Dudek, A.M.D., Witjes, J.A., Heijden, A.G. van der, Vrieling, A., Galesloot, T.E., Juan, A. de, Panadero, A., Rivera, F., Hurst, C., Bishop, D.T., Sak, S.C., Choudhury, A., Teo, M.T., Arici, C., Carta, A., Toninelli, E., Verdier, P. de, Rudnai, P., Gurzau, E, Koppova, K., Keur, K.A. van der, Lurkin, I., Goossens, M., Kellen, E., Guarrera, S., Russo, A., Critelli, R., Sacerdote, C., Vineis, P., Krucker, C., Zeegers, M.P., Gerullis, H., Ovsiannikov, D., Volkert, F., Hengstler, J.G., Selinski, S., Magnusson, O.T., Masson, G., Kong, A., Gudbjartsson, D., Lindblom, A., Zwarthoff, E., Porru, S., Golka, K., Buntinx, F., Matullo, G., Kumar, R., Mayordomo, J.I., Steineck, D.G., Kiltie, A.E., Jonsson, E., Radvanyi, F., Knowles, M.A., Thorsteinsdottir, U., Kiemeney, B., Stefansson, K., Rafnar, T., Sulem, P., Thorleifsson, G., Vermeulen, S., Helgason, H., Saemundsdottir, J., Gudjonsson, S.A., Sigurdsson, A., Stacey, S.N., Gudmundsson, J., Johannsdottir, H., Alexiusdottir, K., Petursdottir, V., Nikulasson, S., Geirsson, G., Jonsson, T., Aben, K.K.H., Grotenhuis, A.J., Verhaegh, G.W.C.T., Dudek, A.M.D., Witjes, J.A., Heijden, A.G. van der, Vrieling, A., Galesloot, T.E., Juan, A. de, Panadero, A., Rivera, F., Hurst, C., Bishop, D.T., Sak, S.C., Choudhury, A., Teo, M.T., Arici, C., Carta, A., Toninelli, E., Verdier, P. de, Rudnai, P., Gurzau, E, Koppova, K., Keur, K.A. van der, Lurkin, I., Goossens, M., Kellen, E., Guarrera, S., Russo, A., Critelli, R., Sacerdote, C., Vineis, P., Krucker, C., Zeegers, M.P., Gerullis, H., Ovsiannikov, D., Volkert, F., Hengstler, J.G., Selinski, S., Magnusson, O.T., Masson, G., Kong, A., Gudbjartsson, D., Lindblom, A., Zwarthoff, E., Porru, S., Golka, K., Buntinx, F., Matullo, G., Kumar, R., Mayordomo, J.I., Steineck, D.G., Kiltie, A.E., Jonsson, E., Radvanyi, F., Knowles, M.A., Thorsteinsdottir, U., Kiemeney, B., and Stefansson, K.

Abstract

Contains fulltext : 138103.pdf (Publisher’s version ) (Closed access), Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 x 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.

Published
2014

4. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.

Author

Kiemeney, L.A.L.M., Sulem, P., Besenbacher, S., Vermeulen, S., Sigurdsson, A., Thorleifsson, G., Gudbjartsson, D.F., Stacey, S.N., Gudmundsson, J., Zanon, C., Kostic, J., Masson, G., Bjarnason, H., Palsson, S., Skarphedinsson, O.B., Gudjonsson, S.A., Witjes, J.A., Grotenhuis, A.J., Verhaegh, G.W.C.T., Bishop, D.T., Sak, S.C., Choudhury, A., Elliott, F., Barrett, J.H., Hurst, C.D., Verdier, P. de, Ryk, C., Rudnai, P., Gurzau, E, Koppova, K., Vineis, P., Polidoro, S., Guarrera, S., Sacerdote, C., Campagna, M., Placidi, D., Arici, C., Zeegers, M.P., Kellen, E., Gutierrez, B.S., Sanz-Velez, J.I., Sanchez-Zalabardo, M., Valdivia, G., Garcia-Prats, M.D., Hengstler, J.G., Blaszkewicz, M., Dietrich, H., Ophoff, R.A., Berg, L.H. van den, Alexiusdottir, K., Kristjansson, K., Geirsson, G., Nikulasson, S., Petursdottir, V., Kong, A., Thorgeirsson, T.E., Mungan, N.A., Lindblom, A., Es, M.A. van, Porru, S., Buntinx, F., Golka, K., Mayordomo, J.I., Kumar, R., Matullo, G., Steineck, G., Kiltie, A.E., Aben, K.K.H., Jonsson, E., Thorsteinsdottir, U., Knowles, M.A., Rafnar, T., Stefansson, K., Kiemeney, L.A.L.M., Sulem, P., Besenbacher, S., Vermeulen, S., Sigurdsson, A., Thorleifsson, G., Gudbjartsson, D.F., Stacey, S.N., Gudmundsson, J., Zanon, C., Kostic, J., Masson, G., Bjarnason, H., Palsson, S., Skarphedinsson, O.B., Gudjonsson, S.A., Witjes, J.A., Grotenhuis, A.J., Verhaegh, G.W.C.T., Bishop, D.T., Sak, S.C., Choudhury, A., Elliott, F., Barrett, J.H., Hurst, C.D., Verdier, P. de, Ryk, C., Rudnai, P., Gurzau, E, Koppova, K., Vineis, P., Polidoro, S., Guarrera, S., Sacerdote, C., Campagna, M., Placidi, D., Arici, C., Zeegers, M.P., Kellen, E., Gutierrez, B.S., Sanz-Velez, J.I., Sanchez-Zalabardo, M., Valdivia, G., Garcia-Prats, M.D., Hengstler, J.G., Blaszkewicz, M., Dietrich, H., Ophoff, R.A., Berg, L.H. van den, Alexiusdottir, K., Kristjansson, K., Geirsson, G., Nikulasson, S., Petursdottir, V., Kong, A., Thorgeirsson, T.E., Mungan, N.A., Lindblom, A., Es, M.A. van, Porru, S., Buntinx, F., Golka, K., Mayordomo, J.I., Kumar, R., Matullo, G., Steineck, G., Kiltie, A.E., Aben, K.K.H., Jonsson, E., Thorsteinsdottir, U., Knowles, M.A., Rafnar, T., and Stefansson, K.

Abstract

Contains fulltext : 87396.pdf (publisher's version ) (Closed access)

Published
2010

5. Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

Author

Stacey, S.N., Sulem, P., Zanon, C., Gudjonsson, S.A., Thorleifsson, G., Helgason, A., Jonasdottir, A., Besenbacher, S., Kostic, J.P., Fackenthal, J.D., Huo, D., Adebamowo, C., Ogundiran, T., Olson, J.E., Fredericksen, Z.S., Wang, X., Look, M.P., Sieuwerts, A.M., Martens, J.W., Pajares, I., Garcia-Prats, M.D., Ramon-Cajal, J.M., Juan, A. de, Panadero, A., Ortega, E., Aben, K.K.H., Vermeulen, S., Asadzadeh, F., Engelenburg, K.C.A. van, Margolin, S., Shen, C.Y., Wu, P.E., Forsti, A., Lenner, P., Henriksson, R., Johansson, R., Enquist, K., Hallmans, G., Jonsson, T., Sigurdsson, H., Alexiusdottir, K., Gudmundsson, J., Sigurdsson, A., Frigge, M.L., Gudmundsson, L., Kristjansson, K., Halldorsson, B.V., Styrkarsdottir, U., Gulcher, J.R., Hemminki, K., Lindblom, A., Kiemeney, L.A.L.M., Mayordomo, J.I., Foekens, J.A., Couch, F.J., Olopade, O.I., Gudbjartsson, D.F., Thorsteinsdottir, U., Rafnar, T., Johannsson, O.T., Stefansson, K., Stacey, S.N., Sulem, P., Zanon, C., Gudjonsson, S.A., Thorleifsson, G., Helgason, A., Jonasdottir, A., Besenbacher, S., Kostic, J.P., Fackenthal, J.D., Huo, D., Adebamowo, C., Ogundiran, T., Olson, J.E., Fredericksen, Z.S., Wang, X., Look, M.P., Sieuwerts, A.M., Martens, J.W., Pajares, I., Garcia-Prats, M.D., Ramon-Cajal, J.M., Juan, A. de, Panadero, A., Ortega, E., Aben, K.K.H., Vermeulen, S., Asadzadeh, F., Engelenburg, K.C.A. van, Margolin, S., Shen, C.Y., Wu, P.E., Forsti, A., Lenner, P., Henriksson, R., Johansson, R., Enquist, K., Hallmans, G., Jonsson, T., Sigurdsson, H., Alexiusdottir, K., Gudmundsson, J., Sigurdsson, A., Frigge, M.L., Gudmundsson, L., Kristjansson, K., Halldorsson, B.V., Styrkarsdottir, U., Gulcher, J.R., Hemminki, K., Lindblom, A., Kiemeney, L.A.L.M., Mayordomo, J.I., Foekens, J.A., Couch, F.J., Olopade, O.I., Gudbjartsson, D.F., Thorsteinsdottir, U., Rafnar, T., Johannsson, O.T., and Stefansson, K.

Abstract

Contains fulltext : 88175.pdf (publisher's version ) (Open Access), We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Published
2010

6. Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus

Author

Stacey, SN, Sulem, P, Zanon, C, Gudjonsson, SA, Thorleifsson, G, Helgason, A, Jonasdottir, A, Besenbacher, S, Kostic, JP, Fackenthal, JD, Huo, D, Adebamowo, C, Ogundiran, T, Olson, JE, Fredericksen, ZS, Wang, XS, Look, Maxime, Sieuwerts, Anieta, Martens, John, Pajares, I, Garcia-Prats, MD, Ramon-Cajal, JM, de Juan, A, Panadero, A, Ortega, E, Aben, KKH, Vermeulen, SH, Asadzadeh, F, van Engelenburg, KCA, Margolin, S, Shen, CY, Wu, PE, Forsti, A, Lenner, P, Henriksson, R, Johansson, R, Enquist, K, Hallmans, G, Jonsson, T, Sigurdsson, H, Alexiusdottir, K, Gudmundsson, J, Sigurdsson, A, Frigge, ML, Gudmundsson, L, Kristjansson, K, Halldorsson, BV, Styrkarsdottir, U, Gulcher, JR, Hemminki, K, Lindblom, A, Kiemeney, LA, Mayordomo, JI, Foekens, John, Couch, FJ, Olopade, OI, Gudbjartsson, DF, Thorsteinsdottir, U, Rafnar, T, Johannsson, OT, Stefansson, K, Stacey, SN, Sulem, P, Zanon, C, Gudjonsson, SA, Thorleifsson, G, Helgason, A, Jonasdottir, A, Besenbacher, S, Kostic, JP, Fackenthal, JD, Huo, D, Adebamowo, C, Ogundiran, T, Olson, JE, Fredericksen, ZS, Wang, XS, Look, Maxime, Sieuwerts, Anieta, Martens, John, Pajares, I, Garcia-Prats, MD, Ramon-Cajal, JM, de Juan, A, Panadero, A, Ortega, E, Aben, KKH, Vermeulen, SH, Asadzadeh, F, van Engelenburg, KCA, Margolin, S, Shen, CY, Wu, PE, Forsti, A, Lenner, P, Henriksson, R, Johansson, R, Enquist, K, Hallmans, G, Jonsson, T, Sigurdsson, H, Alexiusdottir, K, Gudmundsson, J, Sigurdsson, A, Frigge, ML, Gudmundsson, L, Kristjansson, K, Halldorsson, BV, Styrkarsdottir, U, Gulcher, JR, Hemminki, K, Lindblom, A, Kiemeney, LA, Mayordomo, JI, Foekens, John, Couch, FJ, Olopade, OI, Gudbjartsson, DF, Thorsteinsdottir, U, Rafnar, T, Johannsson, OT, and Stefansson, K

Abstract

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case: control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2x10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9x10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9x10(-7)), was without significant heterogeneity between ancestries (P-het = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[ T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Published
2010

7. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

Author

Stacey, S.N., Manolescu, A., Sulem, P., Thorlacius, S., Gudjonsson, S.A., Jonsson, G.F., Jakobsdottir, M., Bergthorsson, J.T., Gudmundsson, J., Aben, K.K.H., Strobbe, L.J., Swinkels, D.W., Engelenburg, K.C.A. van, Henderson, B.E., Kolonel, L.N., Marchand, L. le, Millastre, E., Andres, R., Saez, B., Lambea, J., Godino, J., Polo, E., Tres, A., Picelli, S., Rantala, J., Margolin, S., Jonsson, T., Sigurdsson, H., Jonsdottir, T., Hrafnkelsson, J., Johannsson, J., Sveinsson, T., Myrdal, G., Grimsson, H.N., Sveinsdottir, S.G., Alexiusdottir, K., Saemundsdottir, J., Sigurdsson, A., Kostic, J., Gudmundsson, L., Kristjansson, K., Masson, G., Fackenthal, J.D., Adebamowo, C., Ogundiran, T., Olopade, O.I., Haiman, C.A., Lindblom, A., Mayordomo, J.I., Kiemeney, L.A.L.M., Gulcher, J.R., Rafnar, T., Thorsteinsdottir, U., Johannsson, O.T., Kong, A., Stefansson, K., Stacey, S.N., Manolescu, A., Sulem, P., Thorlacius, S., Gudjonsson, S.A., Jonsson, G.F., Jakobsdottir, M., Bergthorsson, J.T., Gudmundsson, J., Aben, K.K.H., Strobbe, L.J., Swinkels, D.W., Engelenburg, K.C.A. van, Henderson, B.E., Kolonel, L.N., Marchand, L. le, Millastre, E., Andres, R., Saez, B., Lambea, J., Godino, J., Polo, E., Tres, A., Picelli, S., Rantala, J., Margolin, S., Jonsson, T., Sigurdsson, H., Jonsdottir, T., Hrafnkelsson, J., Johannsson, J., Sveinsson, T., Myrdal, G., Grimsson, H.N., Sveinsdottir, S.G., Alexiusdottir, K., Saemundsdottir, J., Sigurdsson, A., Kostic, J., Gudmundsson, L., Kristjansson, K., Masson, G., Fackenthal, J.D., Adebamowo, C., Ogundiran, T., Olopade, O.I., Haiman, C.A., Lindblom, A., Mayordomo, J.I., Kiemeney, L.A.L.M., Gulcher, J.R., Rafnar, T., Thorsteinsdottir, U., Johannsson, O.T., Kong, A., and Stefansson, K.

Abstract

Contains fulltext : 70749.pdf (publisher's version ) (Closed access), We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Published
2008

9. Patients satisfaction with the cancer notebook

Author

Fridriksdottir, N., primary, Sigurdardottir, J., additional, Alexiusdottir, K., additional, Elisdottir, J., additional, Emilsdottir, A.L., additional, Erlendsdottir, J., additional, Johannsdottir, B., additional, Jonasdottir, H., additional, Roesegaard, A.M., additional, and Sigurjonsdottir, S., additional

Published
2001
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10. Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin.

Author

Rafnar T, Sigurjonsdottir GR, Stacey SN, Halldorsson G, Sulem P, Pardo LM, Helgason H, Sigurdsson ST, Gudjonsson T, Tryggvadottir L, Olafsdottir GH, Jonasson JG, Alexiusdottir K, Sigurdsson A, Gudmundsson J, Saemundsdottir J, Sigurdsson JK, Johannsdottir H, Uitterlinden A, Vermeulen SH, Galesloot TE, Allain DC, Lacko M, Sigurgeirsson B, Thorisdottir K, Johannsson OT, Sigurdsson F, Ragnarsson GB, Isaksson H, Hardardottir H, Gudbjartsson T, Gudbjartsson DF, Masson G, Kiemeney LAML, Ewart Toland A, Nijsten T, Peters WHM, Olafsson JH, Jonsson S, Thorsteinsdottir U, Thorleifsson G, and Stefansson K

Subjects
Alleles, Genotype, Humans, Iceland epidemiology, Mutation, Netherlands epidemiology, Odds Ratio, Polymorphism, Single Nucleotide, United States epidemiology, Carcinoma, Squamous Cell genetics, Genes, BRCA2, Genetic Predisposition to Disease, Lung Neoplasms genetics, Skin Neoplasms genetics, Small Cell Lung Carcinoma genetics
Abstract

Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population., Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database., Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele., Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.

Published
2018
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11. A Genetic Polymorphism in CTLA-4 Is Associated with Overall Survival in Sunitinib-Treated Patients with Clear Cell Metastatic Renal Cell Carcinoma.

Author

Liu X, Swen JJ, Diekstra MHM, Boven E, Castellano D, Gelderblom H, Mathijssen RHJ, Vermeulen SH, Oosterwijk E, Junker K, Roessler M, Alexiusdottir K, Sverrisdottir A, Radu MT, Ambert V, Eisen T, Warren A, Rodríguez-Antona C, García-Donas J, Böhringer S, Koudijs KKM, Kiemeney LALM, Rini BI, and Guchelaar HJ

Subjects
Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Biomarkers, Tumor, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Female, Humans, Male, Middle Aged, Prognosis, Proportional Hazards Models, Protein Kinase Inhibitors therapeutic use, Sunitinib therapeutic use, Survival Analysis, Treatment Outcome, CTLA-4 Antigen genetics, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell mortality, Polymorphism, Single Nucleotide
Abstract

Purpose: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKI). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI. Experimental Design: Twenty-seven single-nucleotide polymorphisms (SNP) in CD274 (PD-L1), PDCD1 (PD-1), and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association ( P < 0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis. Results: CTLA-4 rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender, and Heng prognostic risk group [HR, 0.84; 95% confidence interval (CI), 0.72-0.98; P = 0.028, and HR, 0.73; 95% CI, 0.54-0.99; P = 0.047, respectively]. In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of P < 0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR, 0.83; 95% CI, 0.72-0.95; P = 0.008). Patients with the GG genotype had longer OS (35.1 months) compared with patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found. Conclusions: The G-allele of rs231775 in the CTLA-4 gene is associated with an improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker. Clin Cancer Res; 24(10); 2350-6. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Published
2018
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12. Sequence variant at 4q25 near PITX2 associates with appendicitis.

Author

Kristjansson RP, Benonisdottir S, Oddsson A, Galesloot TE, Thorleifsson G, Aben KK, Davidsson OB, Jonsson S, Arnadottir GA, Jensson BO, Walters GB, Sigurdsson JK, Sigurdsson S, Holm H, Arnar DO, Thorgeirsson G, Alexiusdottir K, Jonsdottir I, Thorsteinsdottir U, Kiemeney LA, Jonsson T, Gudbjartsson DF, Rafnar T, Sulem P, and Stefansson K

Subjects
Alleles, Computational Biology methods, Genotype, Humans, Molecular Sequence Annotation, Odds Ratio, Homeobox Protein PITX2, Appendicitis genetics, Chromosomes, Human, Pair 4, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeodomain Proteins genetics, Transcription Factors genetics
Abstract

Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10 -11 ). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.

Published
2017
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13. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.

Author

Haraldsdottir S, Rafnar T, Frankel WL, Einarsdottir S, Sigurdsson A, Hampel H, Snaebjornsson P, Masson G, Weng D, Arngrimsson R, Kehr B, Yilmaz A, Haraldsson S, Sulem P, Stefansson T, Shields PG, Sigurdsson F, Bekaii-Saab T, Moller PH, Steinarsdottir M, Alexiusdottir K, Hitchins M, Pritchard CC, de la Chapelle A, Jonasson JG, Goldberg RM, and Stefansson K

Subjects
Adult, Aged, Aged, 80 and over, Base Pair Mismatch, Colorectal Neoplasms, Hereditary Nonpolyposis epidemiology, Female, Genetic Predisposition to Disease, Humans, Iceland epidemiology, Male, Middle Aged, Prevalence, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, DNA-Binding Proteins genetics, Founder Effect, Germ-Line Mutation, Mismatch Repair Endonuclease PMS2 genetics
Abstract

Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

Published
2017
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14. Loss-of-function variants in ATM confer risk of gastric cancer.

Author

Helgason H, Rafnar T, Olafsdottir HS, Jonasson JG, Sigurdsson A, Stacey SN, Jonasdottir A, Tryggvadottir L, Alexiusdottir K, Haraldsson A, le Roux L, Gudmundsson J, Johannsdottir H, Oddsson A, Gylfason A, Magnusson OT, Masson G, Jonsson T, Skuladottir H, Gudbjartsson DF, Thorsteinsdottir U, Sulem P, and Stefansson K

Subjects
Aged, Aged, 80 and over, Algorithms, Europe, Female, Gene Frequency, Genome-Wide Association Study methods, Genotype, Humans, Logistic Models, Male, Middle Aged, Models, Genetic, Odds Ratio, Risk Factors, Sequence Analysis, DNA methods, Ataxia Telangiectasia Mutated Proteins genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide, Stomach Neoplasms genetics
Abstract

Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1.

Published
2015
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15. Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer.

Author

Rafnar T, Sulem P, Thorleifsson G, Vermeulen SH, Helgason H, Saemundsdottir J, Gudjonsson SA, Sigurdsson A, Stacey SN, Gudmundsson J, Johannsdottir H, Alexiusdottir K, Petursdottir V, Nikulasson S, Geirsson G, Jonsson T, Aben KK, Grotenhuis AJ, Verhaegh GW, Dudek AM, Witjes JA, van der Heijden AG, Vrieling A, Galesloot TE, De Juan A, Panadero A, Rivera F, Hurst C, Bishop DT, Sak SC, Choudhury A, Teo MT, Arici C, Carta A, Toninelli E, de Verdier P, Rudnai P, Gurzau E, Koppova K, van der Keur KA, Lurkin I, Goossens M, Kellen E, Guarrera S, Russo A, Critelli R, Sacerdote C, Vineis P, Krucker C, Zeegers MP, Gerullis H, Ovsiannikov D, Volkert F, Hengstler JG, Selinski S, Magnusson OT, Masson G, Kong A, Gudbjartsson D, Lindblom A, Zwarthoff E, Porru S, Golka K, Buntinx F, Matullo G, Kumar R, Mayordomo JI, Steineck DG, Kiltie AE, Jonsson E, Radvanyi F, Knowles MA, Thorsteinsdottir U, Kiemeney LA, and Stefansson K

Subjects
Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Jagged-1 Protein, Male, Middle Aged, Polymorphism, Single Nucleotide, Serrate-Jagged Proteins, Calcium-Binding Proteins genetics, Chromosomes, Human, Pair 20 genetics, Intercellular Signaling Peptides and Proteins genetics, Membrane Proteins genetics, Urinary Bladder Neoplasms genetics, White People genetics
Abstract

Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2014
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16. Tumour diploidy and survival in breast cancer patients with BRCA2 mutations.

Author

Tryggvadottir L, Olafsdottir EJ, Olafsdottir GH, Sigurdsson H, Johannsson OT, Bjorgvinsson E, Alexiusdottir K, Stefansson OA, Agnarsson BA, Narod SA, Eyfjord JE, and Jonasson JG

Subjects
Adult, Aged, Breast Neoplasms pathology, Female, Humans, Middle Aged, Mutation, Prognosis, BRCA2 Protein genetics, Breast Neoplasms genetics, Diploidy, Survival Analysis
Abstract

It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24-2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91-4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41-1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours.

Published
2013
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17. Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

Author

Stacey SN, Sulem P, Zanon C, Gudjonsson SA, Thorleifsson G, Helgason A, Jonasdottir A, Besenbacher S, Kostic JP, Fackenthal JD, Huo D, Adebamowo C, Ogundiran T, Olson JE, Fredericksen ZS, Wang X, Look MP, Sieuwerts AM, Martens JW, Pajares I, Garcia-Prats MD, Ramon-Cajal JM, de Juan A, Panadero A, Ortega E, Aben KK, Vermeulen SH, Asadzadeh F, van Engelenburg KC, Margolin S, Shen CY, Wu PE, Försti A, Lenner P, Henriksson R, Johansson R, Enquist K, Hallmans G, Jonsson T, Sigurdsson H, Alexiusdottir K, Gudmundsson J, Sigurdsson A, Frigge ML, Gudmundsson L, Kristjansson K, Halldorsson BV, Styrkarsdottir U, Gulcher JR, Hemminki K, Lindblom A, Kiemeney LA, Mayordomo JI, Foekens JA, Couch FJ, Olopade OI, Gudbjartsson DF, Thorsteinsdottir U, Rafnar T, Johannsson OT, and Stefansson K

Subjects
Breast Neoplasms epidemiology, Chromosomes, Human, Pair 6, Female, Genetic Loci, Genetic Predisposition to Disease epidemiology, Humans, Polymorphism, Single Nucleotide, Breast Neoplasms genetics, Estrogen Receptor alpha genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study statistics & numerical data, Racial Groups genetics
Abstract

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping., Competing Interests: All authors from deCODE have equity interests in the company.

Published
2010
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18. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.

Author

Kiemeney LA, Sulem P, Besenbacher S, Vermeulen SH, Sigurdsson A, Thorleifsson G, Gudbjartsson DF, Stacey SN, Gudmundsson J, Zanon C, Kostic J, Masson G, Bjarnason H, Palsson ST, Skarphedinsson OB, Gudjonsson SA, Witjes JA, Grotenhuis AJ, Verhaegh GW, Bishop DT, Sak SC, Choudhury A, Elliott F, Barrett JH, Hurst CD, de Verdier PJ, Ryk C, Rudnai P, Gurzau E, Koppova K, Vineis P, Polidoro S, Guarrera S, Sacerdote C, Campagna M, Placidi D, Arici C, Zeegers MP, Kellen E, Gutierrez BS, Sanz-Velez JI, Sanchez-Zalabardo M, Valdivia G, Garcia-Prats MD, Hengstler JG, Blaszkewicz M, Dietrich H, Ophoff RA, van den Berg LH, Alexiusdottir K, Kristjansson K, Geirsson G, Nikulasson S, Petursdottir V, Kong A, Thorgeirsson T, Mungan NA, Lindblom A, van Es MA, Porru S, Buntinx F, Golka K, Mayordomo JI, Kumar R, Matullo G, Steineck G, Kiltie AE, Aben KK, Jonsson E, Thorsteinsdottir U, Knowles MA, Rafnar T, and Stefansson K

Subjects
Alleles, Disease-Free Survival, Europe, Female, Genotype, Humans, Male, Models, Genetic, Mutation, Receptor, Fibroblast Growth Factor, Type 3 genetics, Recurrence, Risk, Smoking, Chromosomes, Human, Pair 4, Genetic Predisposition to Disease, Genetic Variation, Urinary Bladder Neoplasms genetics
Abstract

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.

Published
2010
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19. Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

Author

Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA, Jonsson GF, Jakobsdottir M, Bergthorsson JT, Gudmundsson J, Aben KK, Strobbe LJ, Swinkels DW, van Engelenburg KC, Henderson BE, Kolonel LN, Le Marchand L, Millastre E, Andres R, Saez B, Lambea J, Godino J, Polo E, Tres A, Picelli S, Rantala J, Margolin S, Jonsson T, Sigurdsson H, Jonsdottir T, Hrafnkelsson J, Johannsson J, Sveinsson T, Myrdal G, Grimsson HN, Sveinsdottir SG, Alexiusdottir K, Saemundsdottir J, Sigurdsson A, Kostic J, Gudmundsson L, Kristjansson K, Masson G, Fackenthal JD, Adebamowo C, Ogundiran T, Olopade OI, Haiman CA, Lindblom A, Mayordomo JI, Kiemeney LA, Gulcher JR, Rafnar T, Thorsteinsdottir U, Johannsson OT, Kong A, and Stefansson K

Subjects
Adenocarcinoma genetics, Adenocarcinoma metabolism, Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Apoptosis, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma, Ductal, Breast genetics, Carcinoma, Ductal, Breast metabolism, Carcinoma, Ductal, Breast pathology, Carcinoma, Intraductal, Noninfiltrating genetics, Carcinoma, Intraductal, Noninfiltrating metabolism, Carcinoma, Intraductal, Noninfiltrating pathology, Carcinoma, Lobular genetics, Carcinoma, Lobular metabolism, Carcinoma, Lobular pathology, Carcinoma, Medullary genetics, Carcinoma, Medullary metabolism, Carcinoma, Medullary pathology, Case-Control Studies, Cohort Studies, Female, Humans, International Agencies, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Receptor, Fibroblast Growth Factor, Type 2 genetics, Receptor, Fibroblast Growth Factor, Type 2 metabolism, Ribosomal Proteins genetics, Ribosomal Proteins metabolism, Breast Neoplasms genetics, Chromosomes, Human, Pair 5 genetics, Genetic Predisposition to Disease, Genetic Variation, Receptors, Estrogen metabolism
Abstract

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Published
2008
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