Increased risk of breast cancer among female relatives of patients with ataxia-telangiectasia: a causal relationship?
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Age Distribution↗
Biomedical subjects
N Andrieu
Publications and source records attributed to N Andrieu.
Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families.
Epidemiological studies have indicated that ataxia-telangiectasia (AT) heterozygotes in AT families have an increased risk of cancer, particularly of breast cancer (BC). However, in BC case-control studies, no significant differences were found in the frequency of ATM mutations between patients and controls. In such studies missense mutations were found more frequently than truncating mutations, suggesting that the cancer risk depends on mutation type. To investigate this possibility, we assessed the risk of BC according to the type and position of the ATM truncating mutation in extended AT families. DNA or RNA that had been isolated from blood or buccal cells of AT children and their relatives was screened for ATM germ-line mutations using restriction endonuclease fingerprinting, the protein truncation test, fluorescence-assisted mismatch analysis, and direct sequencing. The standardized incidence ratio of cancer associated with ATM heterozygosity status and type of mutation was estimated. We tested for genotype-phenotype correlations by simulations, permuting mutations among parental branches. No significant difference was found in the relative risk of breast cancer or any other type of cancer based on mutation type. However, the occurrence of BC may be associated with truncating mutations in certain binding domains of the ATM protein (e.g., P53/BRCA1, beta-adaptin, and FAT domains; P = 0.006). In this limited sample set, the presence of missense or truncating ATM mutations was not associated with different cancer risks. The risk of BC appeared to be associated with the alteration of binding domains rather than with the length of the predicted ATM protein.
Ataxia Telangiectasia↗
The case-combined-control design was efficient in detecting gene-environment interactions.
OBJECTIVE: The interest in studying gene-environment (GxE) interaction is increasing for complex diseases. A design combining both related and unrelated controls (e.g., population-based and siblings) is proposed to increase the power to detect GxE interaction. STUDY DESIGN AND SETTING: We used simulations to assess the efficiency of the case-combined-control design relative to a classical case-control study under a variety of assumptions. RESULTS: The case-combined-control design appears more efficient and feasible than a classical case-control study for detecting interaction involving rare exposures and/or genetic factors. The number of available sibling controls per case and the frequencies of the risk factors are the most important parameters for determining relative efficiency. Relative efficiencies decrease as the frequency of the gene (G) increases. A positive correlation in exposure (E) between siblings decreases relative efficiency. CONCLUSIONS: Although the case-combined-control design may not be efficient for common genes with moderate effects, it appears to be a useful alternative in certain situations where classical approaches remain unrealistic.
Breast Neoplasms↗
Estimation of the familial relative risk of cancer by site from a French population based family study on colorectal cancer (CCREF study).
BACKGROUND: Colorectal cancer (CRC) is the second most common cause of death from cancer in France. A family history of CRC increases an individual's risk of developing CRC. Family history has been suggested to have a greater impact on proximal than distal tumours. AIM: We estimated the familial risk of CRC and other cancers, and examined how risk varies according to localisation of the tumour in the colorectal tract. SUBJECTS: We recorded all cases of CRC diagnosed between 1993 and 1998 in the region served by the Calvados Cancer Registry. A trained interviewer asked all participants about their family history of cancer. STATISTICAL METHODS: Familial risk was estimated from a cohort analysis of the relatives of the CRC cases. The expected numbers of cancers were calculated from Calvados incidence rates. Familial relative risks were calculated using standardised incidence ratios. RESULTS: Our findings showed that colon cancer had a stronger familial/genetic component (relative risk (RR) 1.47) than rectal cancer (RR 0.98). The familial/genetic component appeared stronger for proximal colon cancer than for distal colon cancer only among women (RR 2.24 v RR 1.45). CRC appeared to be positively associated with leukaemia (RR 1.77), stomach cancer (RR 1.32), and testicular cancer (RR 3.13), and negatively associated with urinary bladder cancer (RR 0.57) within families. The cancer spectrum associated with CRC among younger participants included prostate (RR 1.93), uterus (RR 2.49), and thyroid (RR 3.85) cancers. CONCLUSION: If our results are confirmed, follow up guidelines for patients with a family history of CRC should depend on the sex and tumour site of affected relatives to avoid needless invasive screening.
Adult↗
Familial relative risk of colorectal cancer: a population-based study.
This study aimed to assess the familial relative risk for colorectal cancer (CRC) and its variation according to age and gender. A population-based family study was carried out in France, from 1993 to 1998, including 761 families. Familial CRC risks were estimated from a cohort analysis of the relatives. No obvious decrease in CRC risk was found with increasing age, except when either the proband, or the relative, were in the youngest age class. The effect of the relatives' and probands' ages on the CRC risk differed according to their gender. The cumulative risk of CRC increased at an earlier age in male relatives of probands younger than 60 years of age, than in female relatives. This result suggests that mechanisms specific to females, possibly interacting with genetic factors, explain the difference in the cumulative risks between families with male and female probands.
Adolescent↗
Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease.
Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58,515 women with invasive breast cancer and 95,067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19-1.45, P<0.00001) for an intake of 35-44 g per day alcohol, and 1.46 (1.33-1.61, P<0.00001) for >/=45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98-1.07, and for current smokers=0.99, 0.92-1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.
Adult↗
Cancer risk in heterozygotes for ataxia-telangiectasia.
Epidemiological studies have suggested that ataxia-telangiectasia (AT) heterozygotes have a predisposition to cancer, especially breast cancer in women. Now, haplotyping can identify heterozygotes for AT mutation (ATM) in AT families, allowing the risk of cancer associated with ATM heterozygosity status to be better assessed. We report a family study of AT patients, in which we estimated the risk of cancer according to ATM heterozygosity status. We analyzed demographic characteristics and occurrence of cancer in 1,423 relatives of AT patients. Haplotyping was performed in living relatives. The probability of being heterozygotes for ATM was calculated for deceased relatives. The risk of developing cancer was estimated in the cohort of relatives, and expected numbers of cancer cases were calculated from French age period-specific incidence rates. The number of cancers at all sites in the total population of relatives was not higher than expected. However, significant heterogeneity was found according to ATM heterozygosity status. This is mainly due to the increased risk of breast cancer previously observed in obligate heterozygotes. In obligate heterozygotes, relative risk (RR) was non-significantly increased for thyroid cancer, leukemia and liver cancer. Risks of ovarian, lung, pancreatic, kidney, stomach and colorectal cancers were non-significantly increased in the group with 0.5 probability of being heterozygotes. The RR was not significantly increased for any site of cancer, except for breast. Therefore, there is no evidence that specific screening of relatives of AT patients would be justified at particular sites other than the breast. However, the amplitude of the risk of breast cancer estimated in heterozygous women does not appear to justify a separate screening program from that already available to women with a first-degree relative affected by breast cancer.
Ataxia Telangiectasia↗
Counter-matching in studies of gene-environment interaction: efficiency and feasibility.
The interest in studying gene-environment interaction is increasing for complex diseases. However, most methods of detecting gene-environment interactions may not be appropriate for the study of interactions involving rare genes (G:) or uncommon environmental exposures (E:), because of poor statistical power. To increase this power, the authors propose the counter-matching design. This design increases the number of subjects with the rare factor without increasing the number of measurements that must be performed. In this paper, the efficiency and feasibility (required sample sizes) of counter-matching designs are evaluated and discussed. Counter-matching on both G: and E: appears to be the most efficient design for detecting gene-environment interaction. The sensitivity and specificity of the surrogate measures, the frequencies of G: and E:, and, to a lesser extent, the value of the interaction effect are the most important parameters for determining efficiency. Feasibility is also more dependent on the exposure frequencies and the interaction effect than on the main effects of G: and E: Although the efficiency of counter-matching is greatest when the risk factors are very rare, the study of such rare factors is not realistic unless one is interested in very strong interaction effects. Nevertheless, counter-matching appears to be more appropriate than most traditional epidemiologic methods for the study of interactions involving rare factors.
Case-Control Studies↗
Variation in the interaction between familial and reproductive factors on the risk of breast cancer according to age, menopausal status, and degree of familiality.
BACKGROUND: Studies have found that reproductive factors might have a variable effect on the occurrence of breast cancer (BC) according to the existence or not of a family history of BC. The effect of a family history of BC on the risk of BC may also vary according to the age at diagnosis and the degree of kinship. This may confound the relation between familial risk and reproductive factors. A combined analysis was performed to study the interaction between familial risk and reproductive factors according to degree of familiality, age at interview and menopausal status. METHODS: The present analysis included 2948 cases and 4170 controls in seven case-control studies from four countries. The combined relative risks were estimated using a Bayesian random-effects logistic regression model. RESULTS: The main effects of reproductive life factors on the risk of BC are in agreement with previous studies. Two-way interactions between subject's age or menopausal status and a family history of BC were not significant. Although the three-way interaction between age, familial risk and parity was not significant, familial risk seemed to be increased slightly for women with high parity compared with women with low parity in the older age group, and seemed to be slightly decreased for women with high parity compared with women with low parity in younger women. The subject's age also appeared to have an effect on the interaction between familial risk and the age at first childbirth (P = 0.1). CONCLUSIONS: A possible influence of reproductive and menstrual factors on familial risk of BC has been suggested previously and was also evident in the present study. Three-way interactions between age, family history and parity or age at first childbirth might exist and they merit further investigation.
Adult↗
Doxorubicin induces slow ceramide accumulation and late apoptosis in cultured adult rat ventricular myocytes.
OBJECTIVES: Anthracyclines cause apoptotic death in many cell types through activation of the ceramide pathway. We tested the hypothesis that doxorubicin induces cardiac myocyte apoptosis through ceramide generation. METHODS: Adult rat ventricular myocytes were grown in the presence of 10% fetal calf serum, and exposed to 0.5 microM doxorubicin (Dox) for 1 h on the day of cell isolation (day 0). We used the membrane-permeant ceramide analog C2-ceramide (C2-cer) to mimic the effects of endogenous ceramide and PDMP to induce endogenous ceramide accumulation. Apoptosis was assessed upon morphological criteria and DNA fragmentation by the TUNEL method and agarose gel electrophoresis. Ceramide concentration was assessed using the DAG kinase assay. RESULTS: Myocyte exposure to Dox was associated with cellular and nuclear alterations typical of apoptosis on day 7 but not on day 3. At day 7, the percentage of TUNEL-positive myocytes was markedly increased in Dox-treated cultures compared to control (Cl) cultures (82 +/- 3 vs. 12 +/- 1%, n = 7; p < 0.001); internucleosomal DNA fragmentation was confirmed by the observation of DNA ladders. These alterations were associated with an increase in the intracellular ceramide concentration (1715 +/- 243 vs. 785 +/- 99 pmol/mg prot, n = 5; p < 0.01), a phenomenon also detected on day 3 (731 +/- 59 vs. 259 +/- 37 pmol/mg prot, n = 5; p < 0.001). Incubation of myocytes at day 0 with 50 microM C2-cer induced rapid cell shrinkage and DNA fragmentation (45 +/- 3 vs. 10 +/- 1% TUNEL-positive myocytes on day 1 in C2-cer-treated and Cl cultures, respectively; n = 6, p < 0.001). Myocyte exposure to 10 microM PDMP for 7 days (n = 5), caused ceramide accumulation (1.7-fold increase vs. Cl, p < 0.01), and a marked increase in the percentage of TUNEL-positive myocytes (62 +/- 6 vs. 11 +/- 3% in Cl cultures, p < 0.001). Ventricles of rats injected intraperitoneally with a cumulative dose of 14 mg/kg Dox over a period of 2 weeks also showed an increased ceramide concentration 2 weeks later (11.01 +/- 0.64 vs. 5.24 +/- 0.88 pmol/mg prot, n = 6; p < 0.001). CONCLUSION: Our study confirms the existence of a functional ceramide pathway related to apoptosis in cardiac myocytes, and points to its possible involvement in doxorubicin-induced cardiomyopathy.
Animals↗
Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families.
Epidemiological studies in ataxia telangiectasia (AT) families have suggested that AT heterozygotes could have an increased cancer risk, especially breast cancer (BC) in women. It has also been suggested that an increased sensibility of AT heterozygotes to the effect of ionizing radiation could be responsible for the increased BC risk. BC relative risk (RR) estimation in AT heterozygotes within families ascertained through AT children is presented here. Family data collected included demographic characteristics, occurrence of cancers, past radiation exposures and blood samples. DNA samples were studied using seven ATM linked microsatellites markers allowing AT haplotypes reconstitution. The relative risk of BC was assessed using French estimated incidence rates. A significant increase risk of BC is found among obligate ATM heterozygotes with a point estimate of 3.32 (P = 0.002). BC relative risk calculated according to age is significantly increased among the obligate ATM heterozygotes female relatives with an age < or = 44 years (RR = 4.55, P = 0.005). The BC relative risk is statistically borderline among the obligate ATM heterozygote female relatives with an age > or = 45 years (RR = 2.48, P = 0.08). The estimated BC relative risk among ATM heterozygotes is consistent with previously published data. However, the increased risk is only a little higher than classical reproductive risk factors and similar to the risk associated with a first-degree relative affected by BC.
Adolescent↗
Detection of interaction involving identified genes: available study designs.
Advances in molecular genetic techniques have led to an increased ability to examine gene-environment interactions. Studies to detect gene-environment interactions are motivated by different situations, including 1) most identified cancer genes having associated lifetime risks less than 100% (i.e., incomplete penetrance), 2) hereditary factors that control the metabolism of carcinogens that may modulate risk of disease as hypothesized in pharmacogenetics, and 3) inconsistent associations across studies between a cancer and a suspected risk factor. The above situations and others have led to increased study of interaction between genetic and environmental factors. Less studied so far, but with increased potential for the future, is interaction between identified genes. Gene-gene interaction studies would also be motivated by the situations described above. Approaches to detect gene-environment and gene-gene interactions are reviewed. Available risk estimates, required types of subjects, and feasibility of the proposed study designs are discussed; efficiency and power for interaction assessment are summarized where available. In general, most designs allow for estimating risk associated with a genetic factor, environmental factor, and interaction effect. Although power and efficiency for detecting interactions have been assessed for specific situations in some of the methods, further investigations are needed to define the efficiency spectra of each design.
Case-Control Studies↗
The effects of interaction between familial and reproductive factors on breast cancer risk: a combined analysis of seven case-control studies.
In this paper, a combined analysis was performed to study the interaction between familial risk and reproductive life factors. In particular, the interaction between familial risk and breast cell mitotic activity (BCMA), as assessed by duration of ovarian activity, was investigated because of the potential importance of mitotic activity on genetically susceptible cells. The present analysis included 3152 cases and 4404 controls in seven case-control studies from four countries. The interaction effect was estimated in each study separately, then combined using two different methods: a multivariate weighted average and a Bayesian random-effects model. The main effects of reproductive life factors on the risk of breast cancer were in agreement with the previous findings. In particular, an increased duration of BCMA before the first childbirth and over life was found to increase the risk of breast cancer (P < 0.001). Slightly increasing but non-significant, familial risks were observed with increasing number of children (P = 0.17), increasing age at first childbirth (P > 0.2) and increasing duration of BCMA (P > 0.2). There was no modification in familial risk with age at menarche and no clear pattern with menopause characteristics. A weak influence of reproductive and menstrual factors on the familial risk emerged from the present study.
Adult↗
Epidemiologic and genetic approaches in the study of gene-environment interaction: an overview of available methods.
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Case-Control Studies↗
Phospholipase A2 is necessary for tumor necrosis factor alpha-induced ceramide generation in L929 cells.
The role of cytosolic phospholipase A2 (cPLA2) in the regulation of ceramide formation was examined in a cell line (L929) responsive to the cytotoxic action of tumor necrosis factor alpha (TNFalpha). In L929 cells, the addition of TNFalpha resulted in the release of arachidonate, which was followed by a prolonged accumulation of ceramide occurring over 5-12 h and reaching 250% over base line. The formation of ceramide was accompanied by the hydrolysis of sphingomyelin and the activation of three distinct sphingomyelinases (neutral Mg2+-dependent, neutral Mg2+-independent, and acidic enzymes). The variant cell line C12, which lacks cPLA2, is resistant to the cytotoxic action of TNFalpha. TNFalpha was able to activate nuclear factor kappaB in both the wild-type L929 cells and the C12 cells. However, TNFalpha was unable to cause the release of arachidonate or the accumulation of ceramide in C12 cells. C6-ceramide overcame the resistance to TNFalpha and caused cell death in C12 cells to a level similar to that in L929 cells. The introduction of the cPLA2 gene into C12 cells resulted in partial restoration of TNFalpha-induced arachidonate release, ceramide accumulation, and cytotoxicity. This study suggests that cPLA2 is a necessary component in the pathways leading to ceramide accumulation and cell death.
Animals↗
Interactions between genetic and reproductive factors in breast cancer risk in a French family sample.
Considerable progress has been made in the characterization of the genetic component of breast cancer (BC). However, BC still remains a complex disease involving a genetic component and many other risk factors essentially linked to reproductive-life factors. To search for interactions between genetic and reproductive-life factors in the etiology of BC, a systematic family study was performed in two French hospitals from December 1987 to January 1990 and led to recruitment of 288 families, the IGRC data ("IGRC" refers to the Institut Gustave Roussy and Institut Curie, where the data were obtained). Detailed information on reproductive factors was recorded for probands and female first-degree relatives. Segregation analysis of BC was conducted by taking into account a variable age at onset of disease, by use of the class D regressive logistic model, as implemented in the REGRESS computer program. Segregation analyses of BC in IGRC data showed evidence for the segregation of a dominant gene and additional sister-sister dependence, both when reproductive factors were ignored and when they were included. A significant interaction was detected between the dominant gene and age when reproductive factors were taken into account. Among the reproductive factors included in segregation analysis, parity was found to interact with the dominant-gene effect, and there was an indication of an interaction, albeit not significant, between the dominant gene and age at menarche. Whereas the usual protective effect conferred on breast-cancer risk by high parity remained in nonsusceptible women, it disappeared in susceptible women. The increased BC risk associated with a late age at menarche was higher in susceptible women than in nonsusceptible women. Interactions between inherited predisposition to BC and reproductive factors were detected here for the first time by segregation analysis. It would be of major interest to confirm these results by family studies in other populations.
Abortion, Spontaneous↗
The sphingomyelin-ceramide signaling pathway is involved in oxidized low density lipoprotein-induced cell proliferation.
Development of atherosclerosis is believed to involve proliferation of smooth muscle cells (SMC). Our laboratory previously demonstrated that the growth of bovine aortic SMC was stimulated by mildly oxidized low density lipoproteins (oxLDL) and that the mitogenic effect of oxLDL was greater than that induced by native LDL (Augé, N., Pieraggi, M. T., Thiers, J. C., Nègre-Salvayre, A., and Salvayre R.(1995) Biochem. J. 309, 1015-1020). Since the lipid mediator ceramide has been described to be proliferative, the present work aimed at studying the potential involvement of the so-called sphingomyelin-ceramide pathway in the signal transduction cascade induced by oxLDL. Incubation of SMC with UV-oxidized LDL induced sphingomyelin hydrolysis (32%), which peaked at 60 min and was accompanied by a concomitant increase of intracellular ceramide level. The effect of oxidized LDL on sphingomyelin turnover exhibited the same LDL dose dependence as their mitogenic effect. Exogenous bacterial sphingomyelinase induced sphingomyelin hydrolysis and ceramide generation and also stimulated cell growth, in contrast to exogenous phospholipases A2, C, or D. This mitogenic effect was reproduced by incubating the cells with the cell-permeant ceramides, N-acetyl- and N-hexanoylsphingosines. Altogether, these data strongly suggest for the first time that activation of the sphingomyelin-ceramide pathway may play a pivotal role in the oxLDL-induced SMC proliferation and atherogenesis.
Animals↗
Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis.
The nature of the signaling pathway(s) which initiate drug-triggered apoptosis remains largely unknown and is of fundamental importance in understanding cell death induced by chemotherapeutic agents. Here we show that in the leukemic cell lines U937 and HL-60, daunorubicin, at concentrations which trigger apoptosis, stimulated two distinct cycles of sphingomyelin hydrolysis (approximately 20% decrease at 1 microM) within 4-10 min and 60-75 min with concomitant ceramide generation. We demonstrate that the increase in ceramide levels, which precedes apoptosis, is mediated by a neutral sphingomyelinase and not by ceramide synthase. Indeed, potent ceramide synthase inhibitors such as fumonisin B1 did not affect daunorubicin-triggered sphingomyelin hydrolysis, ceramide generation or apoptosis. In conclusion, we provide evidence that daunorubicin-triggered apoptosis is mediated by a signaling pathway which is initiated by an early sphingomyelin-derived ceramide production.
Amidohydrolases↗