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- Abe, O, et al.
(author)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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In: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Journal article (peer-reviewed)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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- Wang, T, et al.
(author)
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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4932-
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Journal article (peer-reviewed)abstract
- Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
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- Meeths, M, et al.
(author)
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Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D
- 2011
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In: Blood. - Washington : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:22, s. 5783-5793
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Journal article (peer-reviewed)abstract
- Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.
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- Mingardo, E, et al.
(author)
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A genome-wide association study with tissue transcriptomics identifies genetic drivers for classic bladder exstrophy
- 2022
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In: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 1203-
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Journal article (peer-reviewed)abstract
- Classic bladder exstrophy represents the most severe end of all human congenital anomalies of the kidney and urinary tract and is associated with bladder cancer susceptibility. Previous genetic studies identified one locus to be involved in classic bladder exstrophy, but were limited to a restrict number of cohort. Here we show the largest classic bladder exstrophy genome-wide association analysis to date where we identify eight genome-wide significant loci, seven of which are novel. In these regions reside ten coding and four non-coding genes. Among the coding genes is EFNA1, strongly expressed in mouse embryonic genital tubercle, urethra, and primitive bladder. Re-sequence of EFNA1 in the investigated classic bladder exstrophy cohort of our study displays an enrichment of rare protein altering variants. We show that all coding genes are expressed and/or significantly regulated in both mouse and human embryonic developmental bladder stages. Furthermore, nine of the coding genes residing in the regions of genome-wide significance are differentially expressed in bladder cancers. Our data suggest genetic drivers for classic bladder exstrophy, as well as a possible role for these drivers to relevant bladder cancer susceptibility.
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- Meeths, M, et al.
(author)
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Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2
- 2010
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 116:15, s. 2635-2643
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Journal article (peer-reviewed)abstract
- Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal hyperinflammatory syndrome characterized by fever, hepatosplenomegaly, cytopenia, and in some cases hemophagocytosis. Here, we describe the mutation analysis, clinical presentation, and functional analysis of natural killer (NK) cells in patients with mutations in STXBP2 encoding Munc18-2, recently associated with familial HLH type 5. The disease severity among 11 persons studied here was highly variable and, accordingly, age at diagnosis ranged from 2 months to 17 years. Remarkably, in addition to typical manifestations of familial HLH (FHL), the clinical findings included colitis, bleeding disorders, and hypogammaglobulinemia in approximately one-third of the patients. Laboratory analysis revealed impairment of NK-cell degranulation and cytotoxic capacity. Interleukin-2 stimulation of lymphocytes in vitro rescued the NK cell–associated functional defects. In conclusion, familial HLH type 5 is associated with a spectrum of clinical symptoms, which may be a reflection of impaired expression and function of Munc18-2 also in cells other than cytotoxic lymphocytes. Mutations in STXBP2 should thus also be considered in patients with clinical manifestations other than those typically associated with HLH.
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- Schoumans, J, et al.
(author)
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Detection and delineation of an unusual 17p11.2 deletion by array-CGH and refinement of the Smith-Magenis syndrome minimum deletion to similar to 650 kb
- 2005
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In: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212. ; 48:3, s. 290-300
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Journal article (peer-reviewed)abstract
- Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome and it is characterized by an interstitial deletion of chromosome 17p11.2. SMS patients have a distinct phenotype which is believed to be caused by haploinsufficiency of one or more genes in the associated deleted region. Five non-deletion patients with classical phenotypic features of SMS have been reported with mutations in the retinoic acid induced I (RAII) gene, located within the SMS critical interval. Happloinsufficiency of the RAII gene is likely to be the responsible gene for the majority of the SMS features, but other deleted genes in the SMS region may modify the overall phenotype in the patients with 17p11.2 deletions. SMS is usually diagnosed in the clinical genetic setting by FISH analysis using commercially available probes. We detected a submicroscopic deletion in 17p11.2 using array-CGH with a resolution of approximately 1 Mb in a patient with the SMS phenotype, who was not deleted for the commercially available SMS microdeletion FISH probe. Delineation of the deletion was performed using a 32K tiling BAC-array, containing 32,500 BAC clones. The deletion in this patient was size mapped to 2.7 Mb and covered the RAII gene. This case enabled the refinement of the SMS minimum deletion to similar to 650 kb containing eight putative genes and one predicted gene. In addition, it demonstrates the importance to investigate deletion of RAII in SMS patients.
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- Tesi, B., et al.
(author)
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Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis
- 2015
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In: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 7:1
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Journal article (peer-reviewed)abstract
- Background: Hemophagocytic lymphohistiocytosis (HLH) is a rapid-onset, potentially fatal hyperinflammatory syndrome. A prompt molecular diagnosis is crucial for appropriate clinical management. Here, we validated and prospectively evaluated a targeted high-throughput sequencing approach for HLH diagnostics. Methods: A high-throughput sequencing strategy of 12 genes linked to HLH was validated in 13 patients with previously identified HLH-associated mutations and prospectively evaluated in 58 HLH patients. Moreover, 2504 healthy individuals from the 1000 Genomes project were analyzed in silico for variants in the same genes. Results: Analyses revealed a mutation detection sensitivity of 97.3 %, an average coverage per gene of 98.0 %, and adequate coverage over 98.6 % of sites previously reported as mutated in these genes. In the prospective cohort, we achieved a diagnosis in 22 out of 58 patients (38 %). Genetically undiagnosed HLH patients had a later age at onset and manifested higher frequencies of known secondary HLH triggers. Rare, putatively pathogenic monoallelic variants were identified in nine patients. However, such monoallelic variants were not enriched compared with healthy individuals. Conclusions: We have established a comprehensive high-throughput platform for genetic screening of patients with HLH. Almost all cases with reduced natural killer cell function received a diagnosis, but the majority of the prospective cases remain genetically unexplained, highlighting genetic heterogeneity and environmental impact within HLH. Moreover, in silico analyses of the genetic variation affecting HLH-related genes in the general population suggest caution with respect to interpreting causality between monoallelic mutations and HLH. A complete understanding of the genetic susceptibility to HLH thus requires further in-depth investigations, including genome sequencing and detailed immunological characterization.
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- Cui, H, et al.
(author)
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Inactivation of H19, an imprinted and putative tumor repressor gene, is a preneoplastic event during Wilms' tumorigenesis
- 1997
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In: Cancer Research. ; 57:20, s. 4469-4473
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Journal article (peer-reviewed)abstract
- Genetic evidence shows that the parent of origin-dependent expression patterns of the Igf2 and H19 genes is coordinated in mouse, such that H19 controls the activity of Igf2 in cis. Equally compelling evidence for a similar situation in humans is absent, although the frequently observed activation of the maternal IGF2 allele (ie., loss of imprinting) in Wilms' tumors has been attributed to the silencing of the maternal H19 locus. We show here that loss of H19 activity is generally a preneoplastic event, which may be linked with an overgrowth lesion that has been proposed to be permissive for tumor formation. Although our results document one instance in which a postneoplastic loss of H19 activity correlates with loss of IGF2 imprinting at the cellular level, it appears that inactivation of H19 is more generally independent of loss of imprinting of IGF2, at least in our specimens. Our results imply that inactivation of H19 correlates with blastema overgrowth and can be independent of a regulatory role with respect to IGF2 imprinting status in cis.
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