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Justo Lorenzo Bermejo

Publications and source records attributed to Justo Lorenzo Bermejo.

At least 19 recordsLinked to original sources
PubMed2006

Association between number of siblings and nervous system tumors suggests an infectious etiology.

OBJECTIVE: To estimate the effect of the number of siblings on the risk of histopathologic subtypes of tumors of the nervous system using large population-based data. METHODS: The Swedish Family-Cancer Database comprises 13,613 diagnoses of nervous system tumors with histopathologic information. We analyzed the data using Poisson regression models taking into account potential confounding effects of age, birth cohort, socioeconomic status, and family history of cancer. RESULTS: The rate ratios (RR) for having four or more siblings vs none were significantly increased for hemangioblastoma (RR = 1.68), childhood neuroblastoma (RR = 2.01), and ependymoma (RR = 1.83, p trend < 0.01). For age at diagnosis < or =15 years, the RRs for individuals with three or more younger siblings compared to none were 1.34 for astrocytoma, 2.30 for medulloblastoma, 2.61 for ependymoma, 3.71 for meningioma, and 2.13 for neuroblastoma, with significant trends in risk. Non-significant decreased risks were found between the number of older siblings and nervous system tumors. CONCLUSIONS: We provide the first reliable quantification of the effects of number of siblings on the risk of nervous system tumors. Sibship size and number of younger siblings correlate with the incidence of childhood nervous system tumors, suggesting a role of infectious agents in the etiology of the disease.

Adolescent↗
PubMed2006

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.

Case-Control Studies↗
PubMed2006

Familial risks and temporal incidence trends of multiple myeloma.

In several cancer registration areas, the trends in the incidence and mortality of multiple myeloma (MM) have been rising over the last few decades. Pedigrees studies on families with multiple affected members have supported the hypothesis of a contributing hereditary etiology of MM due to shared genetic factors. The aim of our study was twofold: 1) to assess incidence trends of MM over the period 1961-2003 using national cancer registry data and; 2) to quantify the familial risk of MM using the 2004 update of the Swedish Family-Cancer Database. For men, the age-standardized rates were 4.33 per 100,000 in 1961-65 and 4.79 in 2001-03. The corresponding rates for women were 2.76 and 3.43. In the elderly, MM rates have risen from 28.7 per 100,000 to 36.2 in men, and from 20.2 to 24.5 in women. MM clustered in families with MM (standardized incidence ratio, SIR=2.45), non-Hodgkin lymphoma (SIR=1.34) and chronic lymphocytic leukaemia (SIR=2.45). No association was found for Hodgkin lymphoma and other leukaemias. Significant associations were found for rectal, stomach, cervical, prostate, bladder, endocrine glands and connective tissue malignancies. Our study adds further evidence that the incidence of MM in Sweden has been constant for several decades. The apparent increase observed in the elderly is, at least in part, attributable to improved diagnostics and certification. MM aggregates in families with MM, chronic lymphocytic leukaemia and, to a lesser extent, with non-Hodgkin lymphoma. If environmental factors can be excluded, the pattern of familial risk of MM is consistent with an autosomal dominant mode of inheritance.

Adult↗
PubMed2006

Polymorphisms in the growth hormone receptor: a case-control study in breast cancer.

The human growth hormone receptor (GHR) mediates the effects of growth hormone (GH1), starting a signalling cascade that is involved in the regulation of proliferation, differentiation and apoptosis. Recently, an isoform of the GHR gene lacking exon 3 (GHRd3) was associated with accelerated responsiveness to growth hormone. In this study, we investigated the association of the GHRd3 polymorphism with breast cancer risk and performed a haplotype analysis with 3 additional single nucleotide polymorphisms (SNPs) (Gly186Gly, Cys440Phe and Ile544Leu) in the GHR coding region in a Polish cohort. We did not observe any effect of the 4 polymorphisms on breast cancer risk. Neither did the 3 most common haplotypes influence breast cancer risk. However, a rare haplotype (dGGC), containing the GHRd3 allele, was associated with a decreased breast cancer risk (OR 0.30, 95% CI 0.11-0.80).

Adult↗
PubMed2006

Single nucleotide polymorphisms in DNA repair genes and basal cell carcinoma of skin.

In addition to environmental exposures like UV radiation and, in some cases, arsenic contamination of drinking water, genetic factors may also influence the individual susceptibility to basal cell carcinoma of skin (BCC). In the present study, 529 cases diagnosed with BCC and 533 controls from Hungary, Romania and Slovakia were genotyped for one polymorphism in each of seven DNA repair genes. The variant allele for T241M (C>T) polymorphism in the XRCC3 gene was associated with a decreased cancer risk [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.61-0.88; P = 0.0007, multiple testing corrected P = 0.004]. The risk of multiple BCC was significantly lower among variant allele carriers than in non-carriers (P = 0.04). Men homozygous for the C-allele for E185Q (G>C) polymorphism in the NBS1 gene showed an increased BCC risk (OR, 2.19; 95% CI, 1.23-3.91), but not women (OR, 0.84; 95% CI, 0.49-1.47). In men, the age and nationality adjusted OR for the genotype CC (XRCC3)/CC (NBS1) was 8.79 (95% CI, 2.10-36.8), compared with the genotype TT (XRCC3)/GG (NBS1). The data from this study show overall risk modulation of BCC by variant allele for T241M polymorphism in XRCC3 and gender-specific effect by E185Q polymorphism in NBS1.

Adolescent↗
PubMed2006

The single nucleotide polymorphism IVS1+309 in mouse double minute 2 does not affect risk of familial breast cancer.

The mouse double minute 2 (MDM2) oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. Further, MDM2 overexpression can inhibit DNA double-strand break repair in a p53-independent manner. Recently, it was shown that a single nucleotide polymorphism (SNP) in the MDM2 promoter was associated with an accelerated tumor formation in individuals with a p53 mutation. The present case-control study investigated the association of this SNP (IVS1+309) with the risk and the age of onset of familial breast cancer in patients with unknown p53 mutation status. Data from 549 women affected by familial breast cancer and 1,065 healthy controls were analyzed. The cases did not carry BRCA1/2 mutations. Cases and controls showed a similar genotype distribution and the SNP did not seem to modify the age of onset of familial breast cancer. The data were also examined taking into account the presence of any additional cancer after breast cancer and the family history of cases; however, no association was found. These results suggest that the SNP IVS1+309 alone affects neither the risk nor the age of onset of heritable breast cancer.

Adult↗
PubMed2006

The balance between heritable and environmental aetiology of human disease.

The Human Genome Project and the ensuing International HapMap Project were largely motivated by human health issues. But the distance from a DNA sequence variation to a novel disease gene is considerable; for complex diseases, closing this gap hinges on the premise that they arise mainly from heritable causes. Using cancer as an example of complex disease, we examine the scientific evidence for the hypothesis that human diseases result from interactions between genetic variants and the environment.

Environmental Exposure↗
PubMed2006

Number of siblings and the risk of lymphoma, leukemia, and myeloma by histopathology.

Epidemiologic evidence indicates that several markers of exposure to childhood infections are inversely associated with the risk of childhood leukemia and lymphomas. We used the Swedish Family-Cancer Database to assess the effects of number of siblings on the risk of non-Hodgkin's (n = 7,007) and Hodgkin's lymphomas (n = 3,115), leukemias (n = 7,650), and multiple myeloma (n = 1,492) by histopathology. Poisson regression models included terms for age, sex, family history, period, and socioeconomic index. Having four or more siblings compared with none was associated with an excess risk of childhood acute lymphoblastic leukemia [ALL; rate ratio (RR), 2.11; P(trend) = 0.001], acute monocytic leukemia (RR, 2.51; P(trend) = 0.002), and multiple myeloma (RR, 1.34; P(trend) = 0.006). Having three or more older siblings compared with none decreased the risk of acute monocytic leukemia (RR, 0.35; P(trend) = 0.001) and childhood ALL (RR, 0.69; P(trend) = 0.01). The risk of Hodgkin's lymphoma for five or more older siblings compared with none was 0.41 (P(trend) = 0.003). Acute myeloid leukemia, chronic lymphocytic leukemia, and other lymphoproliferative malignancies were not associated with number of siblings. In conclusion, we found an excess risk of childhood ALL and acute monocytic leukemia in large families. However, for ALL, acute monocytic leukemia, and Hodgkin's lymphoma, younger siblings were strongly protected compared with older siblings. The remarkable protective effect of number of older siblings on acute monocytic leukemia is a novel finding of potential interest. Possible interpretations of our findings in the context of a putative infectious etiology are discussed.

Adolescent↗
PubMed2006

Gene-environment interactions in cancer: do they exist?

Single nucleotide polymorphisms (SNPs) are extensively used in case-control studies of practically all cancer types. In addition to the pure genetic studies, gene-environment studies, which simultaneously consider environmental factors, have been increasingly conducted. All SNP studies aim at the identification of the role of inherited cancer susceptibility genes. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data on the heritability of cancer and the importance of environmental factors in cancer etiology, we discuss the likelihood of successful gene-environment studies. The available evidence is not conclusive, but it consistently points to a minor heritable etiology in cancer, which will hamper the success of SNP-based association studies. We use simulation techniques to examine which situations would favor the application of a gene-environment approach instead of the traditional environmental approach in case-control studies. The results show that well-chosen candidate gene with a relatively low allele frequency may improve the power to detect environmental determinants of a disease. However, this advantage is lost when the number of underlying genes increases. We are concerned about an indiscriminate use of genetic tools for cancers, which are mainly environmental in origin. The likelihood of success for SNP-based gene-environment studies increases if established environmental risk factors are tested on proven candidate genes. Enhancing the likelihood that the disease causation is genetic, for example, by selecting familial cases, may increase the power of the studies, and the rareness of those cases calls for collaborative networks.

Cocarcinogenesis↗
PubMed2005

Effects of screening for breast cancer on its age-incidence relationships and familial risk.

Mammographic screening programs for breast cancer have been implemented in many countries and opportunistic mammographies are taken as a diagnostic method. The consequences of the wide application of this technology to age-incidence relationships in breast cancer have not been clarified nor is its effect on familial risk estimation. It was assumed that if screening and diagnostic methods bias familial risk, the highest risk should be noted for sisters diagnosed close in time. Age-specific incidence data were collected from the EUCAN database and from cancer registries of Finland, Norway and Sweden. The Swedish Family-Cancer Database was used to analyse risks for breast cancer among sisters, depending on the time since the first sister was diagnosed with breast cancer. Age-incidence patterns deviated between Germany, with low mammographic coverage, and Sweden, the Netherlands, the UK and France, with variable levels of coverage. The annual age-incidence patterns in Finland, Norway and Sweden changed in concert with the targeted mammographic service. The risk of breast cancer for women with an affected sister, diagnosed between ages 50 to 64 years, was significantly higher within the same or the subsequent year of the sister's diagnosis compared to 5+ years, accounting for 7.3% of all patients. The ordered increase in age-specific incidence of breast cancer in the women targeted by screening studied suggests that mammographic screening is one important factor responsible for the shift of the age of onset for breast cancer towards middle age. However, the effects on the estimation of familial risk are so far small.

Adult↗
PubMed2005

Relationships between familial risks of cancer and the effects of heritable genes and their SNP variants.

Familial risks for cancer can be used in many ways in guiding gene identification efforts and, more broadly, in understanding cancer etiology. Gene identification efforts may be properly designed and targeted if the familial risks are well characterized and the mode of inheritance is identified. Single nucleotide polymorphisms (SNPs) are extensively used in case-control studies of practically all cancer types. They are used for the identification of inherited cancer susceptibility genes and those that may interact with environmental factors. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data in the nationwide Swedish Family-Cancer Database, we review familial risks for all main cancers and discuss the evidence for a heritable component in cancer. The available evidence, including differences in cancer incidence between regions and temporal changes within regions, indicates that cancer is mainly an environmental disease, with a minor heritable etiology. The large environmental component will hamper the success of SNP-based genetic association studies. Empirical familial risks should be used to evaluate the feasibility of such studies. We develop figures for the assessment of genetic parameters based on familial risks. Such data are helpful in the estimation of the expected genetic effects in cancer. Overall, we consider the likelihood of a successful application of SNPs in gene-environment studies small, unless established environmental risk factors are tested on proven candidate genes.

Environment↗
PubMed2005

TP53-binding protein variants and breast cancer risk: a case-control study.

INTRODUCTION: The TP53-binding protein (53BP1) has been shown to influence TP53-mediated transcriptional activation, thus playing a pivotal role in DNA damage signalling. Genetic aberrations in TP53 and in ATM and CHEK2 predispose to cancer. We have therefore examined the effects of 53BP1 single nucleotide polymorphisms (D353E, G412S, and K1136Q) and the novel 53BP1 6bp deletion (1347_1352delTATCCC) on breast cancer risk. METHODS: Allelic discrimination was performed to investigate the frequencies of 53BP1 D353E, G412S, and K1136Q and of 1347_1352delTATCCC in 353 patients with breast cancer and 960 control individuals. RESULTS: No significant association of 53BP1 D353E, G412S, or K1136Q with breast cancer risk was detected. 53BP1 1347_1352delTATCCC, leading to the loss of an isoleucine and a proline residue, showed a nonsignificant inverse association with breast cancer risk (odds ratio = 0.61, 95% confidence interval = 0.22 to 1.68, P = 0.34). CONCLUSION: The lack of association casts doubt on the putative effects of D353E, G412S, and K1136Q on breast cancer risk. Investigating a larger study cohort might elucidate the influence of the 6bp deletion 1347_1352delTATCCC. Studying the functional effect and the impact of this variant on the risk of other cancers may be revealing.

Adult↗
PubMed2005

Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database.

Non-Hodgkin lymphoma (NHL) consists of a heterogeneous group of tumors. Population-based data on the familial risk for specific histopathologic subtypes have not been established. Such data are useful for clinical counseling and for searching tumor subtypes sharing common genetic pathways. We used the Swedish Family-Cancer Database to calculate standardized incidence ratios (SIRs) for histopathology-specific subtypes of NHL in 4455 offspring with NHL whose parents or siblings were affected with different types of lymphoproliferative malignancies. A familial history of NHL significantly increased the risk for NHL (SIRparent = 1.8; SIRsibling = 1.9) and for diffuse large B-cell lymphoma (SIRparent = 2.3), follicular lymphoma (SIRsibling = 2.3), and B-cell lymphoma not otherwise specified (NOS) (SIRsibling = 3.4). For a parental history of histopathology-specific concordant cancer, the risks were significantly increased for diffuse large B-cell lymphoma (SIR = 11.8), follicular NHL (SIR = 6.1), plasma cell myeloma (SIR = 2.5), and chronic lymphocytic leukemia (SIR = 5.9). Familial clusters for NHL seemed stronger in females and in siblings. Our study provides the first quantification of the familial risks for NHL by histopathology. The present findings give evidence for a strong familial association of NHL, with little differences in the magnitude of risks for various histopathologic subtypes. The patterns of risks in parents and siblings support the hypothesis of an autosomal-dominant component for diffuse large B-cell NHL and a recessive one for follicular NHL.

Adult↗
PubMed2005

Association of NCOA3 polymorphisms with breast cancer risk.

The nuclear receptor coactivator 3 (NCOA3, also known as AIB1) is a coactivator of nuclear receptors like the estrogen receptor. NCOA3 is overexpressed in approximately 60% of primary human breast tumors, and high levels of NCOA3 expression are associated with tamoxifen resistance and worse survival rate. In contrast, NCOA3 deficiency suppresses v-Ha-ras-induced breast cancer initiation and progression in mice. Here, we analyzed the influence of NCOA3 coding single nucleotide polymorphisms on breast cancer risk by performing a case-control study using a German and a Polish study population and identified an association between NCOA3 polymorphisms and breast cancer. A joint analysis of the German and the Polish study population revealed a significant protective effect for the 1758G>C (Q586H) and 2880A>G (T960T) variants. In addition, haplotype analysis showed a protective effect of the 1758C-2880A and 1758G-2880G haplotypes (odds ratio 0.79; 95% confidence interval, 0.67-0.93; P = 0.004). Because of the impact of NCOA3 in antiestrogen therapy resistance, these polymorphisms might also influence therapy outcome in breast cancer.

Acetyltransferases↗
PubMed2005

Single nucleotide polymorphisms (SNPs) are inherited from parents and they measure heritable events.

Single nucleotide polymorphisms (SNPs) are extensively used in case-control studies of practically all cancer types. They are used for the identification of inherited cancer susceptibility genes and those that may interact with environmental factors. However, being genetic markers, they are applicable only on heritable conditions, which is often a neglected fact. Based on the data in the nationwide Swedish Family-Cancer Database, we review familial risks for all main cancers and discuss the evidence for a heritable component in cancer. The available evidence is not conclusive but it is consistent in pointing to a minor heritable etiology in cancer, which will hamper the success of SNP-based association studies. Empirical familial risks should be used as guidance for the planning of SNP studies. We provide calculations for the assessment of familial risks for assumed allele frequencies and gene effects (odds ratios) for different modes of inheritance. Based on these data, we discuss the gene effects that could account for the unexplained proportion of familial breast and lung cancer. As a conclusion, we are concerned about the indiscriminate use of a genetic tool to cancers, which are mainly environmental in origin. We consider the likelihood of a successful application of SNPs in gene-environment studies small, unless established environmental risk factors are tested on proven candidate genes.

Editorial↗
PubMed2005

Prostate cancer screening, changing age-specific incidence trends and implications on familial risk.

The incidence of prostate cancer has increased markedly during the past half century. We used the data from the Swedish Cancer Registry to follow the incidence trends and age-specific incidence up to 2002. Two different patterns in the age-incidence relationships were noted. The first one, prevailing until about 1995, was characterized by a preferential increase in incidence in men older than 70 years. In the second pattern, the increase extended preferentially to younger age groups, and it coincided with an introduction of opportunistic prostate specific antigen (PSA) screening, which was the probable cause of the large upward shift in the incidence between 1998 and 2000. The possible effects of diagnostic methods on familial risk estimates were tested by comparing age and calendar time differences among brothers who were diagnosed with prostate cancer, retrieved from the Swedish Family-Cancer Database. The 2 distributions were very different according to the Wilcoxon rank test (p < 0.0001). The data suggest that a diagnosis of prostate cancer in 1 brother leads to an early diagnosis in a second brother. The data are probably explained by the healthy brother seeking medical advice upon diagnosis in another brother. This effect is likely to bias familial risk estimates.

Adult↗