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Kari Hemminki, Asta Försti, and Jianguang Ji

Reliable data on familial risks are important for clinical counseling and cancer genetics. We wanted to study incidence trends and familial risks for pituitary adenomas and associated tumors through parental and sibling probands, using the nation-wide Swedish Family-Cancer Database on 10.5 million individuals, containing families with parents and offspring. Cancer data were retrieved from the Swedish Cancer Registry from years 1958 to 2002, including 3239 pituitary tumor patients. Familial risk for offspring was defined through standardized incidence ratio (SIR), adjusted for many variables. The incidence of pituitary adenoma has increased moderately from 1958 to the 1990s and declined thereafter. There were only three offspring–parent pairs with a concordant pituitary tumor, the SIR was not significant. Parental skin cancer (SIR 1.60) and leukemia (1.90, chronic lymphatic leukemia 2.59) were associated with offspring pituitary adenoma diagnosed at any age up to 70 years. There was a strong association of pituitary adenomas with nervous system hemangiopericytomas, SIR 182. The only significant association among siblings was between pituitary tumors and breast cancer (1.46). The risk of pituitary adenoma was marginally increased in individuals whose siblings were diagnosed with colorectal cancer. The results suggest an association of pituitary adenomas with nervous system hemangiopericytomas and breast and colorectal cancers, in addition to some other tumor types. Whether these associations can be explained by the recently identified pituitary adenoma predisposing gene, AIP, remains to be established.

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Jianguang Ji, Asta Fôrsti, Jan Sundquist, and Kari Hemminki

The concentrations of endogenous hormones differ between women with twin and singleton births, with a possible influence on the risk of cancer. We used the nationwide Swedish Family-Cancer Database, including 30 409 women with a twin birth, to examine the subsequent risks of breast, endometrial, and ovarian cancers. Relative risks (RRs) were calculated in a log-linear Poisson regression model of person-years as offset. Cancer data were retrieved from the Swedish Cancer Registry; a total of 1010, 210, and 174 women were diagnosed with breast, endometrial, and ovarian cancers respectively, after a twin birth. A significant decrease in the risk of breast cancer was noted among women with a twin birth compared with women with a singleton birth (RR 0.85, 95% confidence interval (CI) 0.74–0.98). The protective effects were observed throughout the intervals after last pregnancy and they were strongest shortly after the last pregnancy in women who delivered a twin birth before 30 years of age. Twin birth did not change the risk of endometrial cancer (1.08, 95% CI 0.79–1.47) but the RR was increased for women with the number of pregnancies ≥4 (1.39, 95% CI 1.11–1.76). The RR for ovarian cancer was 0.95 (95% CI 0.79–1.15). Our study showed that twin births significantly reduced the subsequent risk of breast cancer. However, the associations of twin births with endometrial and ovarian cancers were not substantial.

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Sonali Pechlivanis, Barbara Pardini, Justo Lorenzo Bermejo, Kerstin Wagner, Alessio Naccarati, Ludmila Vodickova, Jan Novotny, Kari Hemminki, Pavel Vodicka, and Asta Försti

Western lifestyle leading to obesity and type 2 diabetes has been associated with increased risk of colorectal cancer (CRC). Diet and related factors may affect the risk by modifying plasma insulin levels. Thus, the inter-individual variation in insulin signaling may play a plausible role in the development of CRC. We hypothesized that functional polymorphisms in the insulin pathway genes INS, INSR, IGFBPI, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with CRC. We studied the association of five single nucleotide polymorphisms (SNPs) with the risk of CRC using a hospital-based case–control design with 712 cases and 748 controls from the Czech Republic. The INSR A-603G promoter SNP, which is located within a known Sp1-binding site, was associated with the risk of CRC, with carriers of the G allele having a decreased risk (odds ratios (OR) 0.71, 95% confidence interval (CI) 0.54–0.93). Carrying the variant allele of the IRS1 Gly972Arg SNP further decreased the risk among the INSR-603G allele carriers (OR 0.28, 95% CI 0.11–0.70). SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. In conclusion, genetic variation in the insulin signaling pathway genes may affect the risk of CRC.

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Anja Rudolph, Juan Sainz, Rebecca Hein, Michael Hoffmeister, Bernd Frank, Asta Försti, Hermann Brenner, Kari Hemminki, and Jenny Chang-Claude

The mechanisms underlying the association of menopausal hormone therapy (MHT) with reduced colorectal cancer (CRC) risk are unknown and the identification of genetic modifiers may yield further insight. We explored the effect modification of MHT-associated CRC risk in postmenopausal women by 47 polymorphisms with known or putative functional relevance in 16 candidate genes related to hormone metabolism (COMT, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP17A1, GSTP, and HSD17B1), transport (ABCB1), and signaling (ESR1, ESR2, SHBG, PGR, and NR1I2). A total of 685 CRC patients and 684 healthy controls from a German population-based case–control study (DACHS) were genotyped. Multiplicative statistical interaction between polymorphisms and ever MHT use as well as duration of use was assessed using multivariate logistic regression. CRC risk associated with ever MHT use as well as with duration was significantly modified by rs1202168 in the transporter gene ABCB1 (P interaction=0.04). The MHT-associated risk reduction was not significant in homozygous non-carriers (odds ratio (OR) ever use=0.84, 95% confidence interval (CI) 0.53–1.34; OR per 5 year duration=0.94, 95% CI 0.83–1.08), while homozygous carriers of the minor T allele had a 57% lower risk with ever use of MHT (95% CI 0.21–0.88) and a 22% lower risk per 5 years of MHT use (95% CI 0.62–0.97). Significant effect modification was also observed for the ESR1_rs910416 polymorphism (P interaction=0.03 for ever use and 0.07 for duration of use), whereby the decreased risk was attenuated in homozygous carriers of the minor C allele (OR ever use=0.87, 95% CI 0.48–1.60, OR per 5 year duration=0.99, 95% CI 0.83–1.18). Results of this exploratory study provide first evidence that polymorphisms in genes related to estrogen transport and signaling may modify MHT-associated CRC risk but warrant replication in an independent population.

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Annika Vaclavicek, Justo Lorenzo Bermejo, Rita K Schmutzler, Christian Sutter, Barbara Wappenschmidt, Alfons Meindl, Marion Kiechle, Norbert Arnold, Bernhard H F Weber, Dieter Niederacher, Barbara Burwinkel, Claus R Bartram, Kari Hemminki, and Asta Försti

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway mediates the signals of a wide range of cytokines, growth factors and hormones. Thus, aberrant activation of the JAK/STAT pathway may predispose to malignancy due to deregulation of proliferation, differentiation or apoptosis. In this study, we investigated whether genetic variation in the JAK2 gene and the STAT gene region (STAT3, STAT5A and STAT5B) is associated with breast cancer (BC) risk. We carried out a case-control study using a German sample set with 441 familial, unrelated BC cases and 552 controls matched by age, ethnicity and geographical region. A second similar set (381 cases, 460 controls) was applied to validate the findings. Haplotypes in the JAK2 gene were not associated with the risk of BC. In the STAT gene region, the rare haplotype CAGCC containing the variant alleles of each single nucleotide polymorphism (SNP) was associated with an increased risk odds ratio (OR = 5.83, 95% confidence interval (CI) 1.51–26.28). According to Akaike’s information criterion, the best model to describe the relationship between the haplotypes and BC was based on the SNPs rs6503691 (STAT5B) and rs7211777 (STAT3). Carriers of the AC haplotype, which represents the variant alleles of both SNPs, were at an increased risk (OR = 1.41, 95% CI 1.09–1.82). A decreased risk was observed for carriers of the AT haplotype (OR = 0.60, 95% CI 0.38–0.94). Furthermore, individuals with the AC/GC diplotype were at a significantly increased risk (OR = 1.88, 95% CI 1.13–3.14). The observed genetic variation may also influence the inter-individual variation in response to STAT-signalling targeted therapy.