Association of smoking and cancer with the risk of venous thromboembolism: the Scandinavian Thrombosis and Cancer cohort

Smoking is a well-established risk factor for cancer, and cancer patients have a high risk of venous thromboembolism (VTE). Conflicting results have been reported on the association between smoking and risk of VTE, and the effect of smoking on VTE-risk in subjects with cancer is scarcely studied. We aimed to investigate the association between smoking and VTE in subjects with and without cancer in a large population-based cohort. The Scandinavian Thrombosis and Cancer (STAC) cohort included 144,952 participants followed from 1993–1997 to 2008–2012. Information on smoking habits was derived from self-administered questionnaires. Active cancer was defined as the first two years following the date of cancer diagnosis. Former smokers (n = 35,890) and those with missing information on smoking status (n = 3680) at baseline were excluded. During a mean follow up of 11 years, 10,181 participants were diagnosed with cancer, and 1611 developed incident VTE, of which 214 were cancer-related. Smoking was associated with a 50% increased risk of VTE (HR 1.49, 95% CI 1.12–1.98) in cancer patients, whereas no association was found in cancer-free subjects (HR 1.07, 95% CI 0.96–1.20). In cancer patients, the risk of VTE among smokers remained unchanged after adjustment for cancer site and metastasis. Stratified analyses showed that smoking was a risk factor for VTE among those with smoking-related and advanced cancers. In conclusion, smoking was associated with increased VTE risk in subjects with active cancer, but not in those without cancer. Our findings imply a biological interaction between cancer and smoking on the risk of VTE

Combined effects of cancer and prothrombotic genotypes on the risk of venous thromboembolism

Venous thromboembolism (VTE), a collective term for deep vein thrombosis and pulmonary embolism, is a severe and multifactorial disease. Heritability has been found to explain up to 60% of VTE events, however, the role of genetics on VTE in cancer is scarcely studied. VTE occurs frequently in cancer patients and is a common cause of morbidity and mortality in this patient group. The aim of the present thesis was to investigate the impact of individual prothrombotic genotypes and the combination of genotypes in a genetic risk score (GRS) on the risk of VTE in cancer patients. Further, VTE may be the first sign of an underlying malignancy, and therefore we also aimed to investigate the effect of prothrombotic genotypes on VTE risk in subjects with an occult (i.e. undetected) cancer. All four papers in the present thesis utilize data from the fourth survey of the Tromsø Study (Tromsø 4), conducted in 1994-1995. The study populations in Paper I and III are also recruited from the second survey of the Nord-Trøndelag Health Study (HUNT 2), conducted in 1995-1997. Paper IV is based on the Scandinavian Thrombosis and Cancer (STAC) Cohort, which consists of merged data from the Tromsø 4 Study, the HUNT 2 Study and the Danish Diet, Cancer and Health (DCH) Study. Participants were followed from date of enrollment (1993-1997) in the different surveys to the date of an incident VTE event, the date of death or migration, or until end of follow-up (2007-2012). All potential cases of incident VTE events and cancer diagnoses during this time-period were recorded. We reported the effect of several single nucleotide polymorphisms (SNPs) on VTE risk in subjects with and without cancer. A SNP of the GP6 gene (rs1613662), affecting platelet adhesion and activation, displayed a decreased risk of VTE in cancer-free subjects, while an increased risk was observed in cancer patients homozygous for GP6 SNP. The genotype was also found to be associated with prothrombotic and metastatic cancers. These findings support a role of platelet reactivity in the pathogenesis of VTE, which may differ according to cancer status. The risk of VTE was also found to increase by the presence of ABO (rs8176719), and risk alleles in F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914) in both cancer-free subjects and in cancer patients. Moreover, a synergistic effect was discovered for the genetic variants of FGG, FVL and ABO in combination with cancer on the VTE risk. We found a dose-response relationship between number of risk alleles in the 5-SNP score (genetic risk score, GRS) and VTE risk in subjects with and without cancer, and the combined effect of cancer and high-number of risk alleles (≥4 risk alleles) yielded a supra-additive effect for the risk of VTE. However, the five prothrombotic genotypes, alone or combined, did not increase the risk of VTE in occult cancer. Our findings suggest that the genetic risk score and prothrombotic genotypes may be useful for identifying cancer patients at increased risk of VTE

D-Dimer Measured At First Venous Thromboembolism Is Associated With Future Risk Of Cancer

D-dimer >5000 ng/ml at incident VTE is associated with a higher risk of subsequent cancer within one and two years. High D-dimer levels are also associated with more aggressive tumor biology and poor prognosis in these patients. As D-dimer is routinely measured in the assessment of suspected VTE, it may be a useful surrogate marker for the presence of an underlying malignancy. Our findings may suggest that high plasma D-dimer at incident VTE diagnosis should be taken into consideration when the decision to screen for underlying cancer is made

Fibrinogen gamma gene rs2066865 and risk of cancer-related venous thromboembolism

Venous thromboembolism (VTE) is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of VTE, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of VTE. Cases with incident VTE (n=640) and a randomly selected age-weighted sub-cohort (n=3,734) were derived from a population-based cohort (the Tromsø study). Cox-regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for VTE according to categories of cancer and FGG. In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7, 95% CI: 1.2–2.3) increased risk of VTE compared to non-carriers. Cancer patients homozygous for the FGG variant had a two-fold (HR 2.0, 95% CI: 1.1–3.6) higher risk of VTE than cancer patients without the variant. Moreover, the six-months cumulative incidence of VTE among cancer patients was 6.4% (95% CI: 3.5–11.6) in homozygous carriers of FGG and 3.1% (95% CI: 2.3–4.7) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (synergy index: 1.81, 95% CI: 1.02–3.21, attributable proportion: 0.43, 95% CI: 0.11–0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded a synergistic effect on the risk of VTE

Biotechnologia i informacja o biotechnologii

Background - The role of combined prothrombotic genotypes in cancer‐related venous thromboembolism (VTE) is scarcely studied. We aimed to investigate the impact of a 5‐single nucleotide polymorphism (SNP) score on the risk of VTE in patients with and without cancer using a population‐based case‐cohort. Methods - Cases with a first VTE (n = 1493) and a subcohort (n = 13 072) were derived from the Tromsø Study (1994‐2012) and the Nord‐Trøndelag Health Study (1995‐2008). Five SNPs previously reported as a risk score were genotyped: ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914). Hazard ratios (HRs) for VTE were estimated according to cancer status and the number of risk alleles in the 5‐SNP score (0‐1, 2‐3, and ≥4 alleles). Results - During a median follow‐up of 12.3 years, 1496 individuals were diagnosed with cancer, of whom 232 experienced VTE. The VTE risk increased with the number of risk alleles in the 5‐SNP score among subjects without and with cancer. In cancer‐free subjects, the HR was 2.17 (95% confidence interval [CI] 1.79‐2.62) for ≥4 versus 0‐1 risk alleles. In cancer patients, the corresponding HR was 1.93 (95% CI 1.28‐2.91). The combination of cancer and ≥4 risk alleles yielded a 17‐fold (HR 17.1, 95% CI 12.5‐23.4) higher risk of VTE compared with cancer‐free subjects with 0‐1 risk alleles. Conclusion - The risk of VTE increases with the number of prothrombotic risk alleles in subjects with and without cancer, and the combination of prothrombotic risk alleles and cancer leads to a highly elevated risk of VTE

Genetic Variation Of Platelet Glycoprotein VI And The Risk Of Venous Thromboembolism

Family studies have indicated that heritability explains 50-60% of the venous thromboembolism (VTE) events, and in recent years, several single nucleotide polymorphisms (SNPs) have been found to influence the VTE risk. Glycoprotein 6 (GP6) rs1613662, also known as T13254C, is an A/G single nucleotide variation in amino acid 219, which results in a serine to proline substitution affecting the glycoprotein VI (GPVI) receptor for collagen. Platelets carrying the minor allele (G-allele/Pro219) at GP6 rs1613662 express fewer GPVI receptors, which leads to attenuated platelet adhesion and activation. Previous observational studies in selected populations have consistently demonstrated that carriers of the A-allele at GP6 have a 15% higher risk of VTE than non-carriers, and inversely, that G-allele carriers have a 20% lower VTE risk

Prothrombotic genotypes and risk of venous thromboembolism in occult cancer

Background - Studies have reported that the combination of some prothrombotic genotypes and overt cancer yields a synergistic effect on VTE risk. Whether individual prothrombotic genotypes or number of risk alleles in a genetic risk score (GRS) affect VTE risk in occult cancer have not been addressed. The aim of this study was to investigate the joint effect of five prothrombotic genotypes and occult cancer on VTE risk. Methods - Cases with incident VTE (n = 1566) and a subcohort (n = 14,537) were sampled from the Scandinavian Thrombosis and Cancer Cohort (1993–2012). Five single nucleotide polymorphisms previously reported in a GRS were genotyped: ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914). Hazard ratios (HRs) for VTE by individual SNPs and GRS were estimated according to non-cancer and occult cancer (one year preceding a cancer diagnosis) exposure. Results - Occult cancer occurred in 1817 subjects, and of these, 93 experienced a VTE. The VTE risk was 4-fold higher (HR 4.05, 95% CI 3.28–5.00) in subjects with occult cancer compared with those without cancer. Among subjects with occult cancer, those with VTE had a higher proportion of prothrombotic and advanced cancers than those without VTE. The VTE risk increased according to individual prothrombotic genotypes and GRS in cancer-free subjects, while no such effect was observed in subjects with occult cancer (HR for ≥4 versus ≤1 risk alleles in GRS: 1.14, 95% CI 0.61–2.11). Conclusions - Five well-established prothrombotic genotypes, individually or combined, were not associated with increased risk of VTE in individuals with occult cancer

Fibrinogen gamma gene rs2066865 and risk of cancer-related venous thromboembolism

Venous thromboembolism is a frequent complication in patients with cancer. Homozygous carriers of the fibrinogen gamma gene (FGG) rs2066865 have a moderately increased risk of venous thromboembolism, but the effect of the FGG variant in cancer is unknown. We aimed to investigate the effect of the FGG variant and active cancer on the risk of venous thromboembolism. Cases with incident venous thromboembolism (n= 640) and a randomly selected age-weighted sub-cohort (n=3734) were derived from a population-based cohort (the Tromso study). Cox-regression was used to estimate hazard ratios with 95% confidence intervals for VTE according to categories of cancer and FGG. In those without cancer, homozygosity at the FGG variant was associated with a 70% (HR 1.7 95% CI 1.2-2.3) increased risk of venous thromboembolism compared to non-carriers. Cancer patients homozygous for the FGG variant had a 2-fold (HR 2.0 95% CI 1.1-3.6) higher risk of venous thromboembolism than cancer patients without the variant. Moreover, the 6-month cumulative incidence of venous thromboembolism among cancer patients was 6.4% (95% CI, 3.5%-11.6%) in homozygous carriers of FGG and 3.1% (95% CI, 2.3%-4.7%) in those without risk alleles. A synergistic effect was observed between rs2066865 and active cancer on the risk of VTE (Synergy index: 1.81, 95% CI: 1.02-3.21, Attributable proportion: 0.43, 95% CI: 0.11-0.74). In conclusion, homozygosity at the FGG variant and active cancer yielded synergistic effect on the risk of venous thromboembolism

Survival after Cancer-related Venous Thrombosis:the Scandinavian Thrombosis and Cancer Study

Patients with cancer have an increased risk of developing venous thromboembolism (VTE), and this combination is reported to result in poorer survival compared with cancer alone. This study aimed to investigate the impact of VTE on the survival of patients with cancer in a general population. The Scandinavian Thrombosis and Cancer (STAC) cohort, a population-based cohort including 144 952 participants without previous VTE or cancer, was used. During follow-up, cancer and VTE incidences were registered. “Cancer-related VTE” was defined as VTE diagnosed in patients with overt or occult cancer. The survival of participants without cancer and/or VTE (“disease-free”) was compared with the survival of participants with cancer and cancer-related VTE. Cox regression models with cancer and VTE as time-varying exposures were performed to calculate hazard ratios for death. Subanalyses were performed across cancer types and stages and VTE type (deep vein thrombosis or pulmonary embolism). During follow-up (mean, 11.7 years), 14 621 participants developed cancer, and 2444 developed VTE, of which 1241 were cancer-related. The mortality rates (per 100 person years) for disease-free participants, VTE only, cancer only, and cancer-related VTE were 0.63, 5.0, 9.2, and 45.3, respectively. Compared with patients with cancer only, the risk of death for patients with cancer-related VTE was increased 3.4-fold. Within all cancer types, the occurrence of VTE increased the mortality risk 2.8- to 14.7-fold. In a general population, patients with cancer with VTE had a 3.4-fold higher mortality risk than patients with cancer without VTE, independent of cancer type