Publications by authors named "Thorvaldur Jonsson"

30 Publications

  • Page 1 of 1

In situ breast cancer incidence patterns in Iceland and differences in ductal carcinoma in situ treatment compared to Sweden.

Sci Rep 2020 10 19;10(1):17623. Epub 2020 Oct 19.

Landspitali, The National University Hospital of Iceland, Reykjavík, Iceland.

The purpose was to review the incidence of in situ carcinoma in Iceland after initiating population-based mammography screening in 1987 and to compare management of ductal carcinoma in situ (DCIS) between Iceland and the Uppsala-Örebro region (UÖR) in Central Sweden. The Icelandic Cancer Registry provided data on in situ breast carcinomas for women between 1957 and 2017. Clinical data for women with DCIS between 2008 and 2014 was extracted from hospital records and compared to women diagnosed in UÖR. In Iceland, in situ carcinoma incidence increased from 7 to 30 per 100 000 women per year, following the introduction of organised mammography screening. The proportion of in situ carcinoma of all breast carcinomas increased from 4 to 12%. More than one third (35%) of women diagnosed with DCIS in Iceland were older than 70 years versus 18% in UÖR. In Iceland, 49% of all DCIS women underwent mastectomy compared to 40% in UÖR. The incidence of in situ carcinoma in Iceland increased four-fold after the uptake of population-based mammography screening causing considerable risk of overtreatment. Differences in treatment of DCIS were seen between Iceland and UÖR, revealing the importance of quality registration for monitoring patterns of management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-74134-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572374PMC
October 2020

[Comparison of diagnosis and treatment of invasive breast cancer between Iceland and Sweden].

Laeknabladid 2020 Sep;106(9):397-402

University Hospital of Iceland, Reykjavík, Iceland.

Purpose: As part of the implementation of quality registration in Iceland we used retrospective data to compare diagnosis and treatment of invasive breast cancer between Iceland and Sweden.

Materials And Methods: Information on all patients diagnosed with invasive breast cancer in Iceland 2016-2017 was obtained from the Icelandic Cancer Registry. Hospital records were used to register variables in an electronic form adapted from the Swedish quality registration, and compared with data from Sweden for the same period. A chi-square test was used to compare ratios.

Results: A total of 486 cases of breast cancer were diagnosed in Iceland and 15.325 in Sweden. A lower proportion of 40-69 year old women were diagnosed within the screening programme in Iceland (46%) compared to Sweden (60%) (p<0.01). Multidisciplinary tumor board meetings held before and after surgery were less frequent in Iceland (92% vs. 96%) compared to Sweden (98% vs. 99%) in 2016 (p<0,01) but no difference was seen in 2017. A sentinel node surgery was done in 69% of the cases in Iceland compared to 94% in Sweden (p<0,01). For cancers ≤30mm breast conserving surgery was done in 48% cases in Iceland but 80% in Sweden (p<0,01). In Iceland 87% of the cases had radiation therapy after breast conserving surgery but 94% in Sweden (p<0,01). Among mastectomy patients with lymph node metastases, 49% received radiation therapy in Iceland compared to 83% in Sweden (p<0,01).

Conclusion: Differences were seen in several areas of diagnosis and treatment of invasive breast cancer between Iceland and Sweden. With quality registration it will be possible to monitor and set goals for the diagnosis and treatment, with the aim of providing the best treatment to as many patients as possible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.17992/lbl.2020.09.595DOI Listing
September 2020

Common and Rare Sequence Variants Influencing Tumor Biomarkers in Blood.

Cancer Epidemiol Biomarkers Prev 2020 01 30;29(1):225-235. Epub 2019 Oct 30.

deCODE genetics/AMGEN, Reykjavik, Iceland.

Background: Alpha-fetoprotein (AFP), cancer antigens 15.3, 19.9, and 125, carcinoembryonic antigen, and alkaline phosphatase (ALP) are widely measured in attempts to detect cancer and to monitor treatment response. However, due to lack of sensitivity and specificity, their utility is debated. The serum levels of these markers are affected by a number of nonmalignant factors, including genotype. Thus, it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects.

Methods: We performed genome-wide association studies of serum levels of AFP ( = 22,686), carcinoembryonic antigen ( = 22,309), cancer antigens 15.3 ( = 7,107), 19.9 ( = 9,945), and 125 ( = 9,824), and ALP ( = 162,774). We also examined the correlations between levels of these biomarkers and the presence of cancer, using data from a nationwide cancer registry.

Results: We report a total of 84 associations of 79 sequence variants with levels of the six biomarkers, explaining between 2.3% and 42.3% of the phenotypic variance. Among the 79 variants, 22 are cis (in- or near the gene encoding the biomarker), 18 have minor allele frequency less than 1%, 31 are coding variants, and 7 are associated with gene expression in whole blood. We also find multiple conditions associated with higher biomarker levels.

Conclusions: Our results provide insights into the genetic contribution to diversity in concentration of tumor biomarkers in blood.

Impact: Genetic correction of biomarker values could improve prediction algorithms and decision-making based on these biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-18-1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954334PMC
January 2020

Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA.

Nat Commun 2018 11 8;9(1):4568. Epub 2018 Nov 8.

deCODE genetics/AMGEN, 101, Reykjavik, Iceland.

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, r = 0.77 (P = 2.6 × 10), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-06920-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224563PMC
November 2018

Sequence variant at 4q25 near PITX2 associates with appendicitis.

Sci Rep 2017 06 8;7(1):3119. Epub 2017 Jun 8.

deCODE genetics/Amgen, Inc, Reykjavik, 101, Iceland.

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). 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-03353-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465083PMC
June 2017

Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly.

Blood 2017 08 8;130(6):742-752. Epub 2017 May 8.

deCODE genetics/AMGEN, Reykjavik, Iceland.

Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single dominant hematopoietic stem cell lineage. Somatic mutations in candidate driver (CD) genes are thought to be responsible for at least some cases of CH. Using whole-genome sequencing of 11 262 Icelanders, we found 1403 cases of CH by using barcodes of mosaic somatic mutations in peripheral blood, whether or not they have a mutation in a CD gene. We find that CH is very common in the elderly, trending toward inevitability. We show that somatic mutations in , , , and are associated with CH at high significance. However, known CD mutations were evident in only a fraction of CH cases. Nevertheless, the highly prevalent CH we detect associates with increased mortality rates, risk for hematological malignancy, smoking behavior, telomere length, Y-chromosome loss, and other phenotypic characteristics. Modeling suggests some CH cases could arise in the absence of CD mutations as a result of neutral drift acting on a small population of active hematopoietic stem cells. Finally, we find a germline deletion in intron 3 of the telomerase reverse transcriptase () gene that predisposes to CH (rs34002450; = 7.4 × 10; odds ratio, 1.37).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2017-02-769869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553576PMC
August 2017

Why is colon cancer survival improving by time? A nationwide survival analysis spanning 35 years.

Int J Cancer 2017 08 19;141(3):531-539. Epub 2017 May 19.

Department of Pathology, National University Hospital, Reykjavik, Iceland.

There is limited information present to explain temporal improvements in colon cancer survival. This nationwide study investigates the temporal changes in survival over a 35-year period (1970-2004) in Iceland and uses incidence, mortality, surgery rate, stage distribution, lymph node yield, tumor location and histological type to find explanations for these changes. Patients diagnosed with colon cancer in Iceland 1970-2004 were identified (n = 1962). All histopathology was reassessed. Proportions, age-standardized incidence and mortality, relative, cancer-specific and overall survival and conditional survival were calculated. When comparing first and last diagnostic periods (1970-1978 and 1997-2004), 5-year relative survival improved by 12% for men and 9% for women. At the same time surgery rate increased by 12% and the proportion of stage I increased by 9%. Stage-stratified, improved 5-year relative survival was mainly observed in stages II and III and coincided with higher lymph node yields, proportional reduction of stage II cancers and proportional increase of stage III cancers, indicating stage migration between these stages. Improvement in 1-year survival was mainly observed in stages III and IV. Five-year survival improvement for patients living beyond 1 year was minimum to none. There were no changes in histology that coincided with neither increased incidence nor possibly influencing improved survival. Concluding, as a novel finding, 1-year mortality, which previously has been identified as an important variable in explaining international survival differences, is in this study identified as also being important in explaining temporal improvements in colon cancer survival in Iceland.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.30766DOI Listing
August 2017

A genome-wide association study yields five novel thyroid cancer risk loci.

Nat Commun 2017 02 14;8:14517. Epub 2017 Feb 14.

Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500HB Nijmegen, The Netherlands.

The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with P<3 × 10): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms14517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5316879PMC
February 2017

[Epidemiology of the two types of gastric adenocarcinoma in Iceland according to the Laurén histological classification 1990-2009].

Laeknabladid 2016 Mar;102(3):125-30

Background: In the mid twentieth century gastric cancer was the most common type of cancer in Iceland. In recent decades, however, the incidence rate of gastric cancer has decreased markedly and currently only represents 2-3% of cancer cases. The Laurén classification system classifies adenocarcinoma into two types, intestinal and diffuse. The main purpose of our study was to describe the epidemiology of the two types of gastric adenocarcinoma in Iceland between the years 1990-2009.

Methods: This is a retrospective cohort study. Information on patients diagnosed with gastric cancer in Iceland between 1990 and 2009 was collected from the population based Cancer Registry. Histological descriptions were reviewed and classified according to the Laurén classification system. The records of patients diagnosed with either having intestinal or diffuse adenocarcinomas were reviewed and epidemiological information gathered.

Results: Between 1990 and 2009, 730 patients were diagnosed with gastric adenocarcinoma in Iceland, 447 had intestinal adenocarcinoma and 168 diffuse adenocarcinoma. Patients diagnosed with diffuse adenocarcinoma were significantly younger at diagnosis than those diagnosed with intestinal adenocarcinoma. The sex ratio for intestinal adenocarcinoma was 2.3:1 (M:F) and 1.1:1 (M:F) for diffuse adenocarcinoma. The incidence of intestinal adenocarcinoma decreased more rapidly than that of diffuse adenocarcinoma during this period (0.92/100,000 vs. 0.12/100,000). Median survival rates of intestinal and diffuse adenocarcinomas were 23.7 and 20.6 months, respectively. The difference in survival was found to be statistically significant. The hazard ratio between the two groups was 1.31 (CI 1.03-1.67), corrected for age, sex, stage, year of diagnosis and surgical outcome (radical, non-radical or no operation).

Conclusion: The overall incidence rate of gastric cancer has decreased dramatically in the past 20 years. However, the reduction is largely limited to the intestinal adenocarcinoma sub-group. We conclude that the Laurén classification predicts prognosis in gastric adenocarcinoma with diffuse adenocarcinoma having worse prognosis.

Key Words: gastric cancer, Laurén classification, survival, incidence. Correspondence: Halla Sif Olafsdottir, [email protected]
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.17992/lbl.2016.03.70DOI Listing
March 2016

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

Nat Genet 2015 Aug 22;47(8):906-10. Epub 2015 Jun 22.

1] deCODE Genetics/Amgen, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3342DOI Listing
August 2015

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

Hum Mol Genet 2014 Oct 26;23(20):5545-57. Epub 2014 May 26.

Mid Yorkshire NHS Trust, Pinderfields Hospital, Wakefield WF1 4DG, UK.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddu264DOI Listing
October 2014

Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits.

Nature 2013 May 5;497(7450):517-20. Epub 2013 May 5.

deCODE Genetics/Amgen, 101 Reykjavik, Iceland.

Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature12124DOI Listing
May 2013

[Results of immediate breast reconstructions at Landspítali-The National University Hospital of Iceland, in 2008-2010].

Laeknabladid 2012 09;98(9):459-63

Department of Surgery, Landspitali-The National University Hospital of Iceland, Iceland.

Introduction: In late 2007, the availability of immediate breast reconstructions increased as a result of the establishment of an oncoplastic breast surgical service at Landspítali-The National University Hospital The aim of this study was to look at the rates and early complications of immediate breast reconstructions in our hospital in 2008-2010 and compare with the results from the UK National Mastectomy and Breast Reconstruction Audit (NMBRA).

Material And Methods: This is a retrospective population-based study, including all women who had immediate breast reconstruction at Landspítali in 2008-2010.

Results: 319 mastectomies and 157 breast reconstructions were performed. Of these, 98 (62%) were immediate, (mean age 49, 29-69). The immediate breast reconstruction rate was therefore 31%, with a respective 55% for patients 50 years old or younger. In comparison, the rate was 5% in 2000-2005. Immediate reconstructions with an extended autologous latissimus dorsi flap were performed in 25 (26%) cases and implant based reconstructions in the remaining (n=73, 74%). Inpatient complications occurred in 12 (12%) patients and 5 needed reoperation (3 post-operative bleeding, 1 skin necrosis, 1 imminent LD-flap failure). Readmission due to complications after discharge occurred in 14 (14%), while 37 (38%) developed mild complications not requiring readmission. The results were comparable to NMBRA, although the rates of autologous flap reconstructions were significantly higher than in this study (63% vs. 26%).

Conclusion: As a result of the establishment of an oncoplastic breast surgical service at Landspítali, the rates of immediate breast reconstruction have increased significantly (from 5% to 31%). The complication rates are low and similar to NMBRA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.17992/lbl.2012.09.450DOI Listing
September 2012

Discovery of common variants associated with low TSH levels and thyroid cancer risk.

Nat Genet 2012 Jan 22;44(3):319-22. Epub 2012 Jan 22.

deCODE Genetics, Reykjavik, Iceland.

To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10(-8) in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; P(combined) = 1.3 × 10(-9)), rs2439302 on 8p12 (OR = 1.36; P(combined) = 2.0 × 10(-9)) and rs116909374 on 14q13.3 (OR = 2.09; P(combined) = 4.6 × 10(-11)), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10(-91)) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.1046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655412PMC
January 2012

A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.

Nat Genet 2011 Sep 25;43(11):1098-103. Epub 2011 Sep 25.

deCODE genetics, Reykjavik, Iceland.

To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263694PMC
September 2011

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

PLoS Genet 2010 Jul 22;6(7):e1001029. Epub 2010 Jul 22.

deCODE Genetics, Reykjavik, Iceland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1001029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2908678PMC
July 2010

Colon cancer in Iceland--a nationwide comparative study on various pathology parameters with respect to right and left tumor location and patients age.

Int J Cancer 2010 Dec;127(11):2645-53

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Increasing evidence suggests genetic, biological and demographical difference between right and left colon cancer. Studies have also indicated age differences in the pathology of colon cancer. There is a scarcity of large-scale studies that closely examine the pathological differences regarding age and tumor location. The aim of our study was to do an extensive comparison of right- and left- sided colon cancers as well as comparing patients <50 years with older patients. A retrospective, population-based study was carried out on all patients with colon cancer in Iceland between 1955 and 2004. A total of 2293 cases were analyzed (1148 men, 1145 women). All histopathology material was re-evaluated. Differences in tumor characteristics between right and left location and younger (<50) and older (≥50) patients was evaluated in particular. Higher TNM-stage, larger tumors, vessel invasion, mucinous type, high grade and expanding tumor border occurred more frequently in right- versus left-sided lesions while annular and polypoid tumors were more common in left-sided tumors (p < 0.05). Young patients had more frequent lymph node metastases, vessel invasion, nonpolypoid lesions and infiltrating tumor border (p < 0.05). Right-sided lesions show more aggressive features, reflected in morphology and stage. Younger patients present more frequently with adverse features than do older patients. Frequency of right- and left-sided colon cancer differs by age with pronounced age-location differences in females. This supports the assumption of differences in etiology and carcinogenesis of right- and left-sided colon cancer, and between young and old patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.25258DOI Listing
December 2010

Parental origin of sequence variants associated with complex diseases.

Nature 2009 Dec;462(7275):868-74

deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland.

Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature08625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746295PMC
December 2009

[Colon cancer in Iceland 1955-2004. Study on epidemiology, histopathology and gender difference].

Laeknabladid 2009 Jun;95(6):423-30

Laeknadeild Hĺ.

Objective: Colon cancer is the third most common cancer in Iceland. The aim of this study was to analyze the epidemiology and histopathology of colon cancer in Iceland, resection rate and the difference between men and women.

Material And Methods: Pathology and autopsy reports for all patients diagnosed with colon cancer between 1955 and 2004 where reviewed. All the histopathology material was re-evaluated. Demographical information and pathological findings were registered. Age-standardized incidence was calculated for both men and women. Gender difference was evaluated. Time trend was evaluated by linear regression.

Results: After re-evaluation 2293 cases remained (1148 males and 1145 females). The incidence increased for men from 7.5, to 22.2/105 and for women from 8.6 to 15.1/105. Most tumors were located in the sigmoid colon (35%). Surgical rate increased from 50% to 85%. Adenocarcinomas where 84% and mucinous adenocarcinoma 7%. Altogether 7% of cases were TNM-stage I, 32% were stage II, 24% stage III, 21% in stage IV and stage was unknown in 16% of cases. Slight gender difference was observed regarding grade, vessel invasion, depth of invasion and anatomic subsite.

Conclusion: Incidence of colon cancer increased considerably, mainly for men. Surgical rate and pathology of colon cancer is similar to that reported elsewhere except that there are somewhat fewer cases in TNM-stage I. Little gender difference was observed in the pathological parameters analysed.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2009

Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche.

Nat Genet 2009 Jun 17;41(6):734-8. Epub 2009 May 17.

deCODE Genetics, Reykjavik, Iceland.

Earlier menarche correlates with shorter adult height and higher childhood body fat. We conducted a genome-wide association study of age at menarche (AAM) on 15,297 Icelandic women. Combined analysis with replication sets from Iceland, Denmark and the Netherlands (N = 10,040) yielded a significant association between rs314280[T] on 6q21, near the LIN28B gene, and AAM (effect = 1.2 months later per allele; P = 1.8 × 10(-14)). A second SNP within the same linkage disequilibrium (LD) block, rs314277, splits rs314280[T] into two haplotypes with different effects (0.9 months and 1.9 months per allele). These variants have been associated with greater adult height. The association with adult height did not account for the association with AAM or vice versa. Other variants, previously associated with height, did not associate significantly with AAM. Given the link between body fat and AAM, we also assessed 11 variants recently associated with higher body mass index (BMI) and 5 of those associated with earlier AAM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.383DOI Listing
June 2009

Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations.

Nat Genet 2009 Apr 6;41(4):460-4. Epub 2009 Feb 6.

deCODE Genetics, Sturlugata 8, Reykjavik, Iceland.

In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 x 10(-27)) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 x 10(-9)). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T(4)) and high concentration of triiodothyronine (T(3)).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664837PMC
April 2009

Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.

Nat Genet 2009 Feb 18;41(2):221-7. Epub 2009 Jan 18.

deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland.

The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525478PMC
February 2009

Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.

Nat Genet 2009 Jan 14;41(1):18-24. Epub 2008 Dec 14.

deCODE Genetics, Reykjavik, Iceland.

Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.274DOI Listing
January 2009

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

Nat Genet 2008 Jun 27;40(6):703-6. Epub 2008 Apr 27.

deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.131DOI Listing
June 2008

Many sequence variants affecting diversity of adult human height.

Nat Genet 2008 May 6;40(5):609-15. Epub 2008 Apr 6.

deCODE Genetics, 101 Reykjavik, Iceland.

Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.122DOI Listing
May 2008

Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.

Nat Genet 2007 Jul 27;39(7):865-9. Epub 2007 May 27.

deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.

Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng2064DOI Listing
July 2007

A population-based study on the familial aggregation of cutaneous malignant melanoma in Iceland.

Eur J Cancer 2006 May 10;42(7):922-6. Epub 2006 Mar 10.

Iceland Genomics Corporation, Snorrabraut 60, 105 Reykjavik, Iceland.

The aim of this study was to characterize the familial nature of cutaneous malignant melanoma (CMM) in Iceland. Risk ratio was used to estimate the risk among relatives of all CMM index cases diagnosed in Iceland over a 45-year period (1955-1999), using data from the National Cancer Registry and a genealogy database that covers the whole of Iceland's population. First-, second-, and third-degree relatives of CMM patients did not have an increased risk of the disease, and no added risk of other types of cancer among relatives was observed, except for thyroid cancer in first-degree male relatives. Seven individuals were diagnosed with two or more primary CMM in this period; none of these individuals had a first or second-degree relative with CMM. Altogether, 2.4% of cases were familial, as defined by commonly used criteria. In conclusion, high-penetrance susceptibility genes do not contribute much to CMM in the Icelandic population. The great majority of CMM cases in Iceland are most likely caused by the interplay between environmental causes and low-risk genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2005.11.029DOI Listing
May 2006

Population-based study of changing breast cancer risk in Icelandic BRCA2 mutation carriers, 1920-2000.

J Natl Cancer Inst 2006 Jan;98(2):116-22

Icelandic Cancer Registry, Skógarhlío 8, Reykjavík, Iceland.

Background: Mutations in the BRCA genes increase the risk of breast cancer. Valid estimates of the magnitude of the lifetime risk of breast cancer in BRCA gene mutation carriers are needed for genetic counseling. Recent results suggest that penetrance has increased in recent birth cohorts. We examined the cumulative breast cancer incidence and mortality before age 70 over a diagnosis period of 80 years in Icelandic women who carried the BRCA2 founder mutation 999del5.

Methods: Information on all breast cancers diagnosed in Iceland since 1911 was obtained from the Icelandic Cancer Registry. Mutation status was determined by molecular analysis of tissue samples for 847 breast cancer probands who were diagnosed from 1921 through 1985 and selected without knowledge of family history of breast cancer. We estimated the cumulative incidence and mortality from breast cancer before age 70 years in BRCA2 mutation carriers from the observed risks in first-degree relatives who were classified according to mutation status of probands and followed-up through 2002. Poisson modeling of these risks was also carried out. All statistical tests were two-sided.

Results: Of the 847 probands, 88 carried the BRCA2 999del5 mutation and 759 did not. According to Poisson modeling, the cumulative incidence of breast cancer before age 70 years in mutation carriers increased from 18.6% (95% CI = 11.0% to 29.5%) in calendar year 1920 to 71.9% (95% CI = 45.9% to 100%) in 2002 (P < .001); in relatives of probands who did not carry the BRCA2 mutation and in the general Icelandic population incidence increased over the same period from 2.6% to 10.7% and from 1.8% to 7.5%, respectively (all increases of approximately fourfold). During the same period, the cumulative risk of death from breast cancer before age 70 years for BRCA2 mutation carriers increased from 12.1% (95% CI = 5.3% to 23.9%) to 26.9% (95% CI = 10.9% to 55.5%) (P = .08). However, because the probands were breast cancer patients and not a random sample from the population, some bias in the estimation of time trends in penetrance cannot be ruled out.

Conclusions: The results indicate that the penetrance of the Icelandic BRCA2 founder mutation increased nearly fourfold in 80 years, whereas the risk of death from breast cancer before age 70 years increased only approximately twofold. Changes in penetrance with time should be considered when penetrance is estimated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djj012DOI Listing
January 2006
-->