Familial renal cell carcinoma from the Swedish Family-Cancer Database

Background

Reliable data on familial risks are important for clinical counselling and cancer genetics.

Objective

To evaluate familial risks for renal cell carcinomas (RCC) through parental and sibling probands in the largest available dataset.

Design, setting, and participants

This study examined the Swedish Family-Cancer Database on 12.2 million individuals, which contains families with parents and offspring. Cancer data were retrieved from the Swedish Cancer Registry for the years 1961-2008, including 8513 patients with RCC.

Measurements

Familial risk for offspring was defined through standardised incidence ratios (SIRs) and adjusted for many variables, including a proxy for smoking and obesity.

Results and limitations

The familial risk for RCCs was 1.75 when a parent and 2.61 when a sibling was diagnosed with any kidney cancer. Also, RCCs were shown to be associated with prostate cancer (PCa) when parents or parents and siblings were diagnosed with PCa. Among siblings, the associations of RCC with melanoma, non-Hodgkin's lymphoma, and urinary bladder and papillary thyroid tumours were found. None of the results differed significantly after excluding the families with cancer pathognomonic of a von Hippel-Lindau (VHL) disease. Limitations of this study include the small number of familial cases (229 familial cases).

Conclusions

The present analysis showed a high familiarity for RCC, and recessive effects may be important for familial aggregation of RCC. As a novel association, offspring RCC was in excess when parents or parents and siblings were diagnosed with PCa. There is familial clustering beyond VHL and the recent low-risk gene that probably explains a small proportion of the observed familial clustering.     

Incidence and mortality in epithelial ovarian cancer by family history of any cancer

BACKGROUND:

Practically all data on familial risk in ovarian and other cancers are based on incident cancer, whereas familiality in cancer mortality is largely unknown. If fatal forms of cancer are a highly familial subtype, then familial risk for mortality may exceed that of incidence, which is relevant for clinical decision making and counseling.

METHODS:

Ovarian cancer patients in the nationwide Swedish Family Cancer Database were classified according to fatal and nonfatal (incident) family history. Familial risks for incident and fatal ovarian cancer were calculated for offspring based on their parental or sibling family history of any cancer using standardized incidence ratios (SIRs) for incidence and standardized mortality ratios (SMRs) for mortality. Offspring without family history were referents.

RESULTS:

The database included 24,757 mothers and 8138 daughters with ovarian cancer. When a mother had ovarian cancer, the SIR for incident ovarian cancer in daughters was 2.69, and when a sister had ovarian cancer it was 3.49. The SMRs for fatal cancer by fatal cancer in probands were 3.39 and 5.80, respectively. For fatal serous cancers among siblings, the SMR was 6.16, compared with 10.01 for the endometrioid type. Ovarian cancer was associated with maternal (SIR, 1.22; SMR, 1.56) and sororal breast cancer (SIR, 1.27). Another discordant association was between ovarian and paternal prostate cancer (SIR, 1.12; SMR, 1.66).

CONCLUSIONS:

Fatal familial risks were higher for concordant ovarian, ovarian‐breast, and ovarian‐prostate cancers than the corresponding incident risks. This may suggest that highly fatal subtypes exist for these cancers, calling for genetic dissection. Cancer 2011. © 2011 American Cancer Society.     

Interaction between functional polymorphic variants in cytokine genes, established risk factors and susceptibility to basal cell carcinoma of skin

Basal cell carcinoma (BCC) of the skin is the most common neoplasm among the Caucasian population of the Western world. Inflammation may result in oxidative stress and contribute to promotion and progression of tumors, including BCC. The role of cytokines, which are inflammatory modulators, in the biology of tumors has been extensively studied and it is well known that they are aberrantly produced by cancer cells, macrophages and other phagocytic cells. Genetic polymorphisms are known in several cytokine genes, which result in altered expression. In the present association study, we investigated the association of 14 functional polymorphisms in 11 cytokines genes with BCC risk in 529 BCC cases and 532 healthy controls. We have also tested the possible interactions between the genetic variants and three known risk factors for BCC: skin complexion, sun effect and skin response to sun exposure. We did not observe any statistically significant association between SNPs and BCC risk. However, we found that, in a subgroup of subjects more prone to skin burns, carriers of at least one copy of the G allele of rs1800629 (TNF) had an increased risk of BCC [odds ratio (OR) = 2.40, 95% confidence interval (CI) 1.38-4.16, P = 0.0005]. Moreover, in subjects less prone to sunburns, we observed that carriers of the C allele of rs1143627 (IL1B) showed a decreased risk (OR = 0.53, 95% CI 0.34-0.82, P = 0.0019). In conclusion, we found that two polymorphisms in inflammatory genes interacting with environmental risk factors could modulate BCC risk.     

Risk of second malignant neoplasms among lymphoma patients with a family history of cancer

Radiotherapy and chemotherapy are known risk factors for second cancers after lymphoma. The role of genetic influences, however, remains largely unknown. We assessed risk of second cancers associated with family history of any cancer in 41,181 patients with Hodgkin lymphoma (HL) (n = 7,476), non-Hodgkin lymphoma (NHL) (n = 25,941), or chronic lymphocytic leukemia (CLL) (n = 7,764), using a large population-based database. Family history of cancer was based on a diagnosis of any cancer in 110,862 first-degree relatives. We found increased relative risk (RR) (1.81, 95% confidence interval (CI): 1.04-3.16) of breast cancer among HL patient with positive (vs. negative) family history of cancer. Among CLL patients with positive (vs. negative) family history of cancer, we observed elevated risks of bladder (RR = 3.53, 95% CI: 1.31-9.55) and prostate cancer (RR = 2.15, 95% CI: 1.17-3.94). For NHL patients with positive (vs. negative) family history of cancer, we observed non-significantly increased risk of non-melanoma skin cancer (RR = 1.94, 95% CI: 0.86-4.38) and lung cancer (RR = 1.99, 95% CI: 0.73-5.39). Our observations suggest that genetic factors, as measured by positive family history of cancer, may be influential risk-factors for selected second tumors following lymphoproliferative disorders.     

Constraints for genetic association studies imposed by attributable fraction and familial risk

Candidate gene studies have become very popular but some of their implicit constraints, such as the familial risk and the population attributable fraction (PAF) conferred by the gene under study, are poorly understood. We model here these parameters for susceptibility genes in terms of genotype relative risk (GRR), allele frequency and statistical power in simulated genetic association studies, assuming 500 or 2000 case-control pairs and different modes of inheritance. The results show that the common association studies on genes with minor allele frequency >10% have sufficient power to detect disease-causing variants conferring PAFs >10%, which can be compared to known genes, such as BRCA1 with a PAF of 1.8%. Yet, common low-risk variants confer low familial relative risks (FRRs), typically <1.1. The models show that candidate gene studies may be able to identify genes conferring close to 100% of the PAF, but they may not explain the empirical FRRs. In order to explain FRRs, rare, high-penetrant genes or interacting combinations of common variants need to be uncovered. However, the candidate gene studies for common alleles do not target this class of genes. The results may challenge the common disease-common variant hypothesis, which posits common variants with low GRRs and large PAFs, however failing to accommodate the empirical FRRs.     

Gene-environment studies: any advantage over environmental studies?

Gene-environment studies have been motivated by the likely existence of prevalent low-risk genes that interact with common environmental exposures. The present study assessed the statistical advantage of the simultaneous consideration of genes and environment to investigate the effect of environmental risk factors on disease. In particular, we contemplated the possibility that several genes modulate the environmental effect. Environmental exposures, genotypes and phenotypes were simulated according to a wide range of parameter settings. Different models of gene-gene-environment interaction were considered. For each parameter combination, we estimated the probability of detecting the main environmental effect, the power to identify the gene-environment interaction and the frequency of environmentally affected individuals at which environmental and gene-environment studies show the same statistical power. The proportion of cases in the population attributable to the modeled risk factors was also calculated. Our data indicate that environmental exposures with weak effects may account for a significant proportion of the population prevalence of the disease. A general result was that, if the environmental effect was restricted to rare genotypes, the power to detect the gene-environment interaction was higher than the power to identify the main environmental effect. In other words, when few individuals contribute to the overall environmental effect, individual contributions are large and result in easily identifiable gene-environment interactions. Moreover, when multiple genes interacted with the environment, the statistical benefit of gene-environment studies was limited to those studies that included major contributors to the gene-environment interaction. The advantage of gene-environment over plain environmental studies also depends on the inheritance mode of the involved genes, on the study design and, to some extend, on the disease prevalence.     

Sibling risk of Pediatric Obstructive Sleep Apnea Syndrome and Adenotonsillar Hypertrophy

Objectives:

To estimate sibling risk of hospitalization for children with sleep disordered breathing (SDB), diagnosed with (1) obstructive sleep apnea syndrome (OSAS), or (2) adenotonsillar hypertrophy in the total Swedish population.

Design, Setting, and Participants:

Using the MigMed database at the Karolinska Institute, we divided the population of Sweden aged 0–18 years into sibling groups based on a shared mother and father and presence of a primary hospital diagnosis of OSAS or adenotonsillar hypertrophy for each individual born between 1978 and 1986, during the follow-up period 1997–2004. Individuals with at least one affected sibling were identified and the incidence rates were computed, using standardized incidence ratios (SIRs) with 95% confidence intervals (CIs). Reference groups were boys and girls with unaffected siblings of 2 or more.

Results:

After accounting for socioeconomic status, age, and geographic region, boys with at least one sibling with OSAS had an increased risk of having OSAS (SIR, 33.2; 95% CI, 16.5–64.8), and in girls the SIR was 40.5 (19.4–81.4). For hypertrophy of the tonsils or hypertrophy of the adenoids and tonsils the corresponding SIRs were 4.53 (3.0–6.8) for boys and 4.94 (3.3–7.4) for girls.

Conclusions

The study indicate an increased sibling risk of sleep disordered breathing in children, which may be due to heritable genes and/or shared environment such as increased awareness among family members or referring doctors. Caregivers should ask parents if siblings have similar symptoms, and thus offer them early treatment.

Citation:

Friberg D; Sundquist J; Li X; Hemminki K; Sundquist K. Sibling risk of pediatric obstructive sleep apnea syndrome and adenotonsillar hypertrophy. SLEEP 2009;32(8):1077-1083.     

Immunochemical Composition of Cryoglobulins Generated in Stroke

Introduction  Cryoglobulins are abnormal immune complexes where both the antigens and the antibodies are immunoglobulins. The ability of cryoglobulins to bind C-reactive protein and low density lipoproteins, activate complement, and stimulate production of tumor necrosis factor-α generates interest in studying cryoglobulins in ischemic stroke. Materials and Methods  We determined blood levels of cryoglobulins in patients with ischemic stroke at different time points of stroke onset and identified the composition of cryoglobulins isolated from the blood on the first day of stroke onset. Results  On days 1–14, significantly elevated levels of cryoglobulins were detected with the maximum level on day 3. Discussion  Determination of immunoglobulin (Ig) content of cryoglobulins revealed the presence of a mixture of polyclonal IgG, IgA, and IgM, C3 complement protein and its activation split products, C1q complement protein, pathogenic lipoprotein-X, and β-lipoprotein. Conclusion  We suggest that cryoglobulins are involved in post-ischemic inflammatory response through activation of the complement cascade and cytokines production.