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  • Goldin, Lynn R, et al. (författare)
  • Familial aggregation and heterogeneity of non-Hodgkin lymphoma in population-based samples
  • 2005
  • Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - American Association for Cancer Research. - 1055-9965. ; 14:10, s. 6-2402
  • Tidskriftsartikel (refereegranskat)abstract
    • The importance of genetic factors in the etiology of non-Hodgkin lymphoma (NHL) is suggested by case-control and cohort studies. Most previous studies have been too small to estimate accurately risks of specific categories of lymphoproliferative malignancies in relatives of NHL cases or to quantify the contribution of NHL case characteristics to familial risk. We have overcome sample size limitations and potential recall bias by using large databases from Sweden and Denmark. Diagnoses of lymphoproliferative malignancies were compared in 70,006 first-degree relatives of 26,089 NHL cases (including 7,432 with subtype information) versus 161,352 first-degree relatives of 58,960 matched controls. Relatives of NHL cases were at significantly increased risk for NHL [relative risk (RR), 1.73; 95% confidence interval (95% CI), 1.39-2.15], Hodgkin lymphoma (RR, 1.41; 95% CI, 1.0-1.97), and nonsignificantly for chronic lymphocytic leukemia (CLL; RR, 1.31; 95% CI, 0.93-1.85). No increased risk was found for multiple myeloma among case relatives. Findings with respect to siblings compared with parents and offspring or with respect to age at diagnosis of proband were inconsistent. In both populations, relatives of cases with an aggressive NHL subtype were at substantially increased risk of NHL (combined RR, 3.56; 95% CI, 1.80-7.02). We conclude that NHL has an important familial component, which is shared with Hodgkin lymphoma and CLL. We estimate that the absolute lifetime risk for a first-degree relative of an NHL case to develop NHL is 3.6% (compared with a population risk of 2.1%) and higher if the index case had an aggressive subtype of NHL.
  • Harlid, Sophia, et al. (författare)
  • A candidate CpG SNP approach identifies a breast cancer associated ESR1-SNP.
  • 2011
  • Ingår i: International Journal of Cancer. - John Wiley and Sons Inc.. - 0020-7136. ; Dec, s. 1689-1698
  • Tidskriftsartikel (refereegranskat)abstract
    • Altered DNA methylation is often seen in malignant cells, potentially contributing to carcinogenesis by suppressing gene expression. We hypothesized that heritable methylation potential might be a risk factor for breast cancer and evaluated possible association with breast cancer for single nucleotide polymorphisms (SNPs) either involving CpG sequences in extended 5'- regulatory regions of candidate genes (ESR1, ESR2, PGR and SHBG) or CpG and missense coding SNPs in genes involved in methylation (MBD1, MECP2, DNMT1, MGMT, MTHFR, MTR, MTRR, MTHFD1, MTHFD2, BHMT, DCTD and SLC19A1). Genome-wide searches for genetic risk factors for breast cancers have in general not investigated these SNPs, because of low minor allele frequency or weak haplotype associations.Genotyping was performed using Mass spectrometry-Maldi-Tof in a screening panel of 538 cases and 1067 controls. Potential association to breast cancer was identified for 15 SNPs and one of these SNPs (rs7766585 in ESR1) was found to associate strongly with breast cancer, OR 1.30 (95% CI 1.17-1.45; p-value 2.1x10(-6)), when tested in a verification panel consisting of 3211 unique breast cancer cases and 4223 unique controls from five European biobank cohorts.In conclusion, a candidate gene search strategy focusing on methylation-related SNPs did identify a SNP that associated with breast cancer at high significance.
  • Harlid, Sophia, et al. (författare)
  • Combined effect of low-penetrant SNPs on breast cancer risk.
  • 2012
  • Ingår i: British Journal of Cancer. - Nature Publishing Group. - 1532-1827. ; 106, s. 389-396
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status.Methods:Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression.Results:Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10(-20) and 1.5 × 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10(-4)).Conclusion:The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.British Journal of Cancer advance online publication, 1 November 2011; doi:10.1038/bjc.2011.461 www.bjcancer.com.
  • Hemminki, Kari, et al. (författare)
  • Cancer of unknown primary (CUP): does cause of death and family history implicate hidden phenotypically changed primaries?
  • 2012
  • Ingår i: Annals of Oncology. - Oxford University Press. - 1569-8041. ; 23:10, s. 2720-2724
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer of unknown primary (CUP) is diagnosed at the metastatic stage. We aimed to identify hidden primary cancers in CUP patients by comparison with cancers in family members. We take use of the fact that the cause of death in CUP patients is often coded as the cancer in the organ of fatal metastasis. Forty-one thousand five hundred and twenty-three CUP patients were identified in the Swedish Family-Cancer Database, and relative risks (RRs) were calculated for cancer in offspring when family members were diagnosed with CUP and died of the cancer diagnosed in offspring. The RR for lung cancer in offspring was 1.85 when a family member was diagnosed with CUP and died of lung cancer. Significant familial associations were found for seven other cancers. Many familial associations were also significant when offspring CUP patients died of the cancer diagnosed in family members. The cause of death after CUP diagnosis frequently matched the cancer found in a family member, suggesting that the CUP had originated in that tissue. The metastasis had probably undergone a phenotypic change, complicating pathological tissue assignment. These novel data suggest that some CUP cases are phenotypically modified primary cancers rather than cancers of unknown primaries.
  • Hemminki, Kari, et al. (författare)
  • Cancer risks in first-generation immigrants to Sweden
  • 2002
  • Ingår i: International Journal of Cancer. - John Wiley and Sons Inc.. - 0020-7136. ; 99:2, s. 28-218
  • Tidskriftsartikel (refereegranskat)abstract
    • We used the nationwide Swedish Family-Cancer Database to analyse cancer risks in 613,000 adult immigrants to Sweden. All the immigrants had become parents in Sweden and their median age at immigration was 24 years for men and 22 years for women. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for 18 cancer sites using native Swedes as a reference. Data were also available from compatriot marriages. All cancer was decreased by 5% and 8% for immigrant men and women, respectively. However, most of the male increase was due to lung cancer for which male immigrants showed a 41% excess. Among individual cancer sites and immigrant countries, 110 comparisons were significant, 62 showing protection and 48 an increased risk. Most of the differences between the rates in immigrants and Swedes could be ascribed to the variation of cancer incidence in the indigenous populations. Some high immigrant SIRs were 5.05 (n = 6, 95% CI 1.82-11.06) for stomach cancer in Rumanian women and 2.41 (41, 1.73-3.27) for lung cancer in Dutch men. At some sites, such as testis, prostate, skin (melanoma), kidney, cervix and nervous system, the SIRs for immigrants were decreased; in some groups of immigrants SIRs were about 0.20. The highest rates for testicular cancer were noted for Danes and Chileans. Women from Yugoslavia and Turkey had an excess of thyroid tumours. All immigrant groups showed breast, endometrial and ovarian cancers at or below the Swedish level but the differences were no more than 2-fold.
  • Hemminki, Kari, et al. (författare)
  • Cancer risks in ulcerative colitis patients
  • 2008
  • Ingår i: International Journal of Cancer. - John Wiley and Sons Inc.. - 0020-7136. ; 123:6, s. 21-1417
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients diagnosed with ulcerative colitis (UC) are known to be at an increased risk of colorectal and liver cancers and leukemia. UC is an autoimmune disease, which may present a wider spectrum of cancers. We wanted to examine the risk of cancer in a large population of UC patients in order to reach high statistical power. A UC research database was constructed by identifying UC patients from the Swedish Hospital Discharge Register and cancer patients from the Cancer Registry. Follow-up of 27,606 UC patients hospitalized for the first time during the years 1964-2004 identified 2,058 patients with cancer. Standardized incidence ratios were calculated for cancer in UC patients by comparing to subjects without hospitalization for UC. The novel tumor sites in UC patients included small intestinal (carcinoid), pancreatic, breast and prostate cancers, nonthyroid endocrine gland tumors, non-Hodgkin lymphoma and multiple myeloma. A total of 11 sites showed an increased risk, which remained at 6 sites when tumors diagnosed in the year of UC hospitalization were excluded; even chronic myeloid leukemia was in excess. Cancer risks depended on the age at first hospitalization for UC. The SIRs for colon, rectal, liver and pancreatic cancers declined by age at hospitalization for UC, while for endocrine tumors the older patients were at higher risk. Our large study identified novel subsequent cancers in UC patients. However, some of these, including small intestinal carcinoids, prostate cancers and nonthyroid endocrine tumors, may be in excess because of intensified medical surveillance of the patients.
  • Hemminki, Kari, et al. (författare)
  • Concordance of survival in family members with prostate cancer
  • 2008
  • Ingår i: Journal of Clinical Oncology. - American Society of Clinical Oncology. - 0732-183X. ; 26:10, s. 9-1705
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Several earlier studies have assessed survival in prostate cancer based on familial risk of this disease. As a novel concept, we posit that factors governing survival in prostate cancer are likely to be different from those governing risk of prostate cancer. To prove this, we searched for familial clustering of survival (ie, concordance of survival among family members).PATIENTS AND METHODS: We used the nationwide Swedish Family-Cancer Database to estimate hazard rates (HRs) for cause-specific and overall survival in invasive prostate cancer. HRs show the probability of death in the study group compared with the reference group. The study covered 610 sons of affected fathers with median follow-up times for survival ranging from 34 to 76 months.RESULTS: When the survival in sons was analyzed according to the fathers' length of survival, there was a concordance of prognosis; the HR was 0.62 for sons whose fathers had survived longer than 59 months, compared with sons whose fathers had survived fewer than 24 months (P for trend, .02). On a continuous scale, the sons' survival increased almost linearly with the fathers' survival time. When the analysis was reversed and HRs were derived for fathers, the concordance of good and poor survival remained.CONCLUSION: The results are consistent in showing that both good and poor survival in prostate cancer aggregate in families. Genetic factors are likely to contribute to the results, which provide the first challenging population-level evidence on heritability in prognosis of prostate cancer.
  • Hemminki, Kari, et al. (författare)
  • Familial Association of Inflammatory Bowel Diseases With Other Autoimmune and Related Diseases
  • 2010
  • Ingår i: American Journal of Gastroenterology. - Wolters Kluwer Health. - 1572-0241. ; 105:1, s. 139-147
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Familial risk estimates are useful for genetic counseling, etiological understanding, and design of gene identification studies. We wanted to estimate the associations of ulcerative colitis (UC) and Crohn's disease (CD) with 32 autoimmune and related diseases among parents and offspring, singleton siblings, twins, and spouses. METHODS: The Multigeneration Register in Sweden provides reliable access to information on families among 11.5 million individuals throughout the last century. The diseases in individual family members were obtained through linkage to the Hospital Discharge Register. Standardized incidence ratios (SIRs) and 95 % confi dence intervals were calculated as relative risks for UC/CD in family members of patients diagnosed with any of the 34 diseases compared with those lacking affected family members through years 1964-2004. RESULTS: Among a total of 441,642 patients diagnosed with autoimmune and related conditions, 25,846 were diagnosed with UC and 18,885 with CD. Familial cases amounted to 5.4 % of all UC patients and 6.5 % of CD patients. SIR for UC was 3.9 (95% confidence interval 3.5 - 4.3) in offspring of affected parents, 4.6 (3.0-7.4) in siblings, 10.4 (6.5-15.8) in families of affected parents and siblings, and 6.3 (1.9-17.7) for monozygotic twins. The respective SIRs for CD were 6.0 (5.4-6.7), 6.3 (4.1-9.8), 34.0 (24.9-45.3), and 23.4 (10.1-51.1). All discordant associations, i. e., those between CD and other diseases, were also found for UC, including ankylosing spondylitis, asthma, polymyalgia rheumatica, psoriasis, and sarcoidosis. For UC, six additional associations were observed. No correlations between specifi c diseases were found among spouses, but between UC or CD and any disease it was 1.1 (1.0-1.1). CONCLUSIONS: The concordant familial risks for UC and CD were lower than those commonly cited. Both diseases are associated with several autoimmune and related diseases, suggesting genetic sharing. Am J Gastroenterol 2010; 105: 139- 147; doi: 10.1038/ ajg. 2009.496; published online 25 August 2009
  • Hemminki, Kari, et al. (författare)
  • Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions
  • 2009
  • Ingår i: Arthritis and Rheumatism. - John Wiley and Sons Inc.. - 0004-3591. ; 60:3, s. 8-661
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: In the era of genome-wide association studies, familial risks are used to estimate disease heritability and the likelihood of candidate-gene identification. This study was undertaken to estimate associations of rheumatoid arthritis (RA) with any of 33 autoimmune diseases and related conditions among parents and offspring, singleton siblings, twins, and spouses.METHODS: The Multigeneration Register in Sweden was used as a reliable source of information on Swedish families throughout the last century. Data on autoimmune diseases in individual family members were obtained through linkage to the Hospital Discharge Register. The standardized incidence ratio (SIR) was calculated as a measure of the relative risk of RA in family members of patients with RA or any of 33 other autoimmune diseases or related conditions, as compared with the relative risk of RA in those lacking an affected family member.RESULTS: Among a total of 447,704 patients, 47,361 were diagnosed as having RA. The SIRs for RA were 3.02 in offspring of affected parents, 4.64 in siblings, 9.31 in multiplex families, 6.48 in twins, and 1.17 in spouses. Significant associations with the familial risk of RA in offspring according to parental proband were observed for ankylosing spondylitis (SIR 2.96), localized scleroderma (SIR 2.40), Sjögren's syndrome (SIR 2.25), systemic lupus erythematosus (SIR 2.13), systemic sclerosis (SIR 1.65), Hashimoto thyroiditis/hypothyroidism (SIR 1.54), pernicious anemia (SIR 1.53), sarcoidosis (SIR 1.40), psoriasis (SIR 1.36), Wegener's granulomatosis (SIR 1.34), and asthma or polymyalgia rheumatica (SIR 1.32).CONCLUSION: This is the first study to compare the familial risks of RA in relation to a large number of autoimmune diseases and related conditions using data from a single population. The high discordant familial risks in this population suggest that there is extensive genetic sharing between RA and the associated diseases.
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