521 research outputs found
Cancer incidence in relatives of British Fanconi Anaemia patients.
No full textBACKGROUND: Fanconi anemia (FA) is an autosomal recessive DNA repair disorder with affected individuals having a high risk of developing acute myeloid leukaemia and certain solid tumours. Thirteen complementation groups have been identified and the genes for all of these are known (FANCA, B, C, D1/BRCA2, D2, E, F, G, I, J/BRIP1, L, M and N/PALB2). Previous studies of cancer incidence in relatives of Fanconi anemia cases have produced conflicting results. A study of British FA families was therefore carried out to investigate this question, since increases in cancer risk in FA heterozygotes would have implications for counselling FA family members, and possibly also for the implementation of preventative screening measures in FA heterozygotes.
METHODS: Thirty-six families took part and data was collected on 575 individuals (276 males, 299 females), representing 18,136 person years. In this cohort, 25 males and 30 females were reported with cancer under the age of 85 years, and 36 cancers (65%) could be confirmed from death certificates, cancer registries or clinical records.
RESULTS: A total of 55 cancers were reported in the FA families compared to an estimated incidence of 56.95 in a comparable general population cohort, and the relative risk of cancer was 0.97 (95% C.I. = 0.71-1.23, p = 0.62) for FA family members. Analysis of relative risk for individual cancer types in each carrier probability group did not reveal any significant differences with the possible exception of prostate cancer (RR = 3.089 (95% C.I. = 1.09 - 8.78; Chi2 = 4.767, p = 0.029).
CONCLUSION: This study has not shown a significant difference in overall cancer risk in FA families
Mutation analysis of the Fanconi Anaemia group A, C, E, F and G genes in sporadic acute myeloid leukaemia
No full textLong-term outcomes of hysterectomy with bilateral salpingo-oophorectomy: a systematic review and meta-analysis
No full textObjective: this study aimed to provide an up-to-date systematic review of “the long-term outcomes of bilateral salpingo-oophorectomy at the time of hysterectomy” and perform a meta-analysis for the reported associations. Data Sources: our study updated a previous systematic review by searching the literature using PubMed, Web of Science, and Embase for publications between January 2015 and August 2022. Study Eligibility Criteria: our study included studies of women who had a hysterectomy with bilateral salpingo-oophorectomy vs women who had a hysterectomy with ovarian conservation or no surgery. Methods: the quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations. Adjusted hazard ratios were extracted and combined to obtain fixed effect estimates. Results: compared with hysterectomy or no surgery, hysterectomy with bilateral salpingo-oophorectomy in young women was associated with decreased risk of breast cancer (hazard ratio, 0.78; 95% confidence interval, 0.73–0.84) but with an increased risk of colorectal cancer (hazard ratio, 1.27; 95% confidence interval, 1.10–1.47). In addition, it was associated with an increased risk of total cardiovascular diseases, coronary heart disease, and stroke with hazard ratios of 1.18 (95% confidence interval, 1.11–1.25), 1.17 (95% confidence interval, 1.10–1.25), and 1.20 (95% confidence interval, 1.10–1.31), respectively. Compared with no surgery, hysterectomy with bilateral salpingo-oophorectomy before the age of 50 years was associated with an increased risk of hyperlipidemia (hazard ratio, 1.44; 95% confidence interval, 1.25–1.65), diabetes mellitus (hazard ratio, 1.16; 95% confidence interval, 1.09–1.24), hypertension (hazard ratio, 1.13; 95% confidence interval, 1.06–1.20), dementia (hazard ratio, 1.70; 95% confidence interval, 1.07–2.69), and depression (hazard ratio, 1.39; 95% confidence interval, 1.22–1.60). The evidence on the association with all-cause mortality in young women showed substantial heterogeneity between the studies (I2=85%; P<.01). Conclusion: hysterectomy with bilateral salpingo-oophorectomy was associated with multiple long-term outcomes. The benefits of the addition of bilateral salpingo-oophorectomy to hysterectomy should be balanced against the risks.</p
A comparison of methods currently used in clinical practice to estimate familial breast cancer risks
No full textBackground: With the identification of genes predisposing to hereditary breast cancer, the accurate and consistent estimation of a woman's risk of developing breast cancer based on her family history is of paramount importance if national service guidelines are to be developed. Patients and methods: The residual lifetime risk of developing breast cancer was estimated for 200 women attending a breast cancer genetic assessment clinic by three different methods currently in use in the UK. Risks were computed on the basis of the Cancer and Steroid Hormone (CASH) study data and were classified as 'low/moderate' (< 20%) or 'high' (>20%). These risk categories are representative of those currently used to allocate surveillance and genetic testing. Risks were then compared to estimates derived by other methods used in current clinical practice, including those of Houlston and Murday. Results: The CASH data-based method ascribed 27% to the high risk category, as compared to 53% for the combined Houlston and Murday methods. A method based on the number of affected relatives alone ascribed only 14% to the high risk category. Overall, 108 (54%) women were placed in the same risk category by all three methods. Conclusions: This study demonstrates that there is a significant degree of variability between methods currently used to estimate breast cancer risk which has serious implications for individual patient management, service provision and multicentre studies evaluating the benefits of genetic testing for breast cancer susceptibility.</p
Deletion and reduced expression of the Fanconi anemia FANCA gene in sporadic acute myeloid leukemia
No full textFanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (P<0.0001). Sequencing FANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML
Are Fanconi Anaemia genes inactivated in sporadic acute myeloid leukemia?
No full textFanconi Anaemia (FA) is an autosomal recessive disorder characterised by congenital abnormalities, defective haemopoesis and a greatly increased risk of Acute Myeloid Leukaemia (AML). We are investigating whether mutations in the FA genes might predispose to the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from peripheral blood or bone marrow from AML cases for deletions in the cloned FA genes, FANCA, C, D2, E, F, G. Of the 103 samples successfully screened for the FANCA gene, four heterozygous deletions were found (see table). Sequence analysis of the other allele in these four cases did not locate a second mutation. A sodium bisulphite conversion assay was developed to detect methylation of the FANCA CpG island. There was no evidence of allele inactivation by hypermethylation in these 4 samples, nor in a further 28 non-deleted samples. No deletions were found on screening the FANCC, D2, E, F and G genes in 64, 68, 31, 42 and 51 samples respectively. FANCA is a large gene (43 exons, 80kb) with a high incidence of deletion mutations in affected FA patients. These results show that such deletions may also be found in sporadic AML and may have contributed to leukaemogenesis
Extending the Benign and Malignant Phenotypes Associated with Germline DICER1 Mutations.
No full textThe influence of genetic variation in thirty selected genes on the clinical characteristics of early onset breast cancer
No full textIntroduction: common variants that alter breast cancer risk are being discovered. Here, we determine how these variants influence breast cancer prognosis, risk and tumour characteristics.Methods: we selected 1,001 women with early onset nonfamilial invasive breast cancer from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort and genotyped 206 single nucleotide polymorphisms (SNPs) across 30 candidate genes. After quality control, 899 cases and 133 SNPs remained. Survival analyses were used to identify SNPs associated with prognosis and determine their interdependency with recognized prognostic factors. To identify SNPs that alter breast cancer risk, association tests were used to compare cases with controls from the Wellcome Trust Case Control Consortium. To search for SNPs affecting tumour biology, cases were stratified into subgroups according to oestrogen receptor (ER) status and grade and tested for association.Results: we confirmed previous associations between increased breast cancer risk and SNPs in CASP8, TOX3 (previously known as TNRC9) and ESR1. Analysis of prognosis identified eight SNPs in six genes (MAP3K1, DAPK1, LSP1, MMP7, TOX3 and ESR1) and one region without genes on 8q24 that are associated with survival. For MMP7, TOX3 and MAP3K1 the effects on survival are independent of the main recognized clinical prognostic factors. The SNP in 8q24 is more weakly associated with independent effects on survival. Once grade and pathological nodal status (pN stage) were taken into account, SNPs in ESR1 and LSP1 showed no independent survival difference, whereas the effects of the DAPK1 SNP were removed when correcting for ER status. Interestingly, effects on survival for SNPs in ESR1 were most significant when only ER-positive tumours were examined. Stratifying POSH cases by tumour characteristics identified SNPs in FGFR2 and TOX3 associated with ER-positive disease and SNPs in ATM associated with ER-negative disease.Conclusions: we have demonstrated that several SNPs are associated with survival. In some cases this appears to be due to an effect on tumour characteristics known to have a bearing on prognosis; in other cases the effect appears to be independent of these prognostic factors. These findings require validatation by further studies in similar patient group
Long-term outcomes of bilateral salpingo-oophorectomy in women with personal history of breast cancer
No full textObjectives: to investigate the association between bilateral salpingo-oophorectomy (BSO) and long-term health outcomes in women with a personal history of breast cancer.Methods and analysis: we used data on women diagnosed with invasive breast cancer between 1995 and 2019 from the National Cancer Registration Dataset (NCRD) in England. The data were linked to the Hospital Episode Statistics-Admitted Patient Care dataset to identify BSO delivery. Long-term health outcomes were selected from both datasets. Multivariable Cox regression was used to examine the associations, with BSO modelled as a time-dependent covariate. The associations were investigated separately by age at BSO.Results: we identified 568 883 women, 23 401 of whom had BSO after the breast cancer diagnosis. There was an increased risk of total cardiovascular diseases with an HR of 1.10 (95% CI 1.04 to 1.16) in women who had BSO<55 years and 1.07 (95% CI 1.01 to 1.13) for women who had BSO≥55 years. There was an increased risk of ischaemic heart diseases, but there was no association with cerebrovascular diseases. BSO at any age was associated with an increased risk of depression (HR 1.20, 95% CI 1.12 to 1.28) and increased risk of second non-breast cancer in older women (HR 1.21, 95%CI 1.08 to 1.35). BSO in older women was associated with reduced risk of all-cause mortality (HR 0.92, 95% CI 0.87 to 096), but not in women who had BSO<55 years.Conclusion: in women with a personal history of breast cancer, BSO before and after the age of 55 years is associated with an increased risk of long-term outcomes. BSO after 55 years is associated with reduced all-cause mortality. Family history or genetic predisposition may confound these associations
Extending the phenotypes associated with DICER1 mutations.
No full textDICER1 is crucial for embryogenesis and early development. Forty different heterozygous germline DICER1 mutations have been reported worldwide in 42 probands that developed as children or young adults, pleuropulmonary blastoma (PPB), cystic nephroma (CN), ovarian sex cord-stromal tumors (especially Sertoli-Leydig cell tumor [SLCT]), and/or multinodular goiter (MNG). We report DICER1 mutations in seven additional families that manifested uterine cervix embryonal rhabdomyosarcoma (cERMS, four cases) and primitive neuroectodermal tumor (cPNET, one case), Wilms tumor (WT, three cases), pulmonary sequestration (PS, one case), and juvenile intestinal polyp (one case). One carrier developed (age 25 years) a pleomorphic sarcoma of the thigh; another carrier had transposition of great arteries (TGA). These observations show that cERMS, cPNET, WT, PS, and juvenile polyps fall within the spectrum of DICER1-related diseases. DICER1 appears to be the first gene implicated in the etiology of cERMS, cPNET, and PS. Young adulthood sarcomas and perhaps congenital malformations such as TGA may also be associated
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