Abstract：
BACKGROUND:Inter-individual differences in dihydropyrimidine dehydrogenase (DPYD encoding DPD) and thiopurine S-methyltransferase (TPMT) activity are important predictors for fluoropyrimidine and thiopurine toxicity. While several variants in these genes are known to decrease enzyme activities, many additional genetic variations with unclear functional consequences have been identified, complicating informed clinical decision-making in the respective carriers. METHODS:We used a novel pharmacogenetically trained ensemble classifier to analyse DPYD and TPMT genetic variability based on sequencing data from 138,842 individuals across eight populations. RESULTS:The algorithm accurately predicted in vivo consequences of DPYD and TPMT variants (accuracy 91.4% compared to 95.3% in vitro). Further analysis showed high genetic complexity of DPD deficiency, advocating for sequencing-based DPYD profiling, whereas genotyping of four variants in TPMT was sufficient to explain >95% of phenotypic TPMT variability. Lastly, we provided population-scale profiles of ethnogeographic variability in DPD and TPMT phenotypes, and revealed striking interethnic differences in frequency and genetic constitution of DPD and TPMT deficiency. CONCLUSION:These results provide the most comprehensive data set of DPYD and TPMT variability published to date with important implications for population-adjusted genetic profiling strategies of fluoropyrimidine and thiopurine risk factors and precision public health.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Zhou Y,Dagli Hernandez C,Lauschke VMdoi
10.1038/s41416-020-01084-0subject
Has Abstractpub_date
2020-12-01 00:00:00pages
1782-1789issue
12eissn
0007-0920issn
1532-1827pii
10.1038/s41416-020-01084-0journal_volume
123pub_type
杂志文章abstract：:Tumour angiogenesis is a complex multistep process regulated by a number of angiogenic factors. One such factor, platelet-derived endothelial cell growth factor has recently been shown to be thymidine phosphorylase (TP). TP catalyses the reversible phosphorylation of thymidine to deoxyribose-1-phosphate and thymine. A...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1996.49
更新日期：1996-02-01 00:00:00
abstract：:The brain-specific angiogenesis inhibitor 1 gene has been isolated in an attempt to find fragments with p53 "functional" binding sites. As reported herein and by others, brain-specific angiogenesis inhibitor 1 expression is present in some normal tissues, but is reduced or lost in tumour tissues. Such data and its par...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6600067
更新日期：2002-02-01 00:00:00
abstract：:The cisplatin analogue 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinum(IV) (DAP) is a DNA-damaging agent that will be entering clinical trials for its potent cytotoxic effects against cisplatin-resistant tumour cells. This cytotoxicity may reside in its ability to selectively activate G1-phase checkpoint r...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6603448
更新日期：2006-12-04 00:00:00
abstract：:In this study we sought factors that determine the survival of human colonic epithelial cells. Normal colonic epithelial cells are dependent on cell-cell contacts and survival factors for the inhibition of apoptosis whereas, during colorectal tumorigenesis, cells develop mechanisms to evade these controls. The ability...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1997.167
更新日期：1997-01-01 00:00:00
abstract：:In haemagglutination tests we have found that the monoclonal antibody B5 discriminates between erythrocytes from patients with malignant cancer (total 386; greater than 80% B5 positive) and individuals with no known tumour (total 247; less than 20% B5 positive). The B5 antigen detected on intact erythrocytes is a tigh...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1984.53
更新日期：1984-03-01 00:00:00
abstract：BACKGROUND:Neuroblastoma is the most common malignancy of infancy but little is known about the aetiological factors associated with the development of this tumour. A number of epidemiological studies have previously examined the risk associated with paternal occupational exposures but most have involved small numbers ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6605504
更新日期：2010-02-02 00:00:00
abstract：BACKGROUND:Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC). METHODS:A total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine foll...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6605348
更新日期：2009-11-03 00:00:00
abstract：:Eighteen patients with inoperable hepatocellular carcinoma (HCC) were treated with intrahepatic arterial yttrium-90 microspheres. All these patients showed a lung shunting below 15% and a tumour-to-normal ratio higher than 2 as determined by diagnostic technetium-99m macroaggregated albumin (Tc-MAA) gamma scintigraphy...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/bjc.1994.436
更新日期：1994-11-01 00:00:00
abstract：:Natural human interferon beta (beta-IFN) was tested during the early phase of in vitro infection with HTLV-I virus of human cord blood mononuclear cells (CBL), to evaluate whether its antiviral and immunomodulating effects might prevent spreading of infection in the host. beta-IFN was found to reduce HTLV-I transmissi...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1988.111
更新日期：1988-05-01 00:00:00
abstract：:Apoptosis is a physiological form of cell death important in normal processes such as morphogenesis and the functioning of the immune system. In addition, defects in the apoptotic process play a major role in a number of important areas of disease, such as autoimmune diseases and cancer. DNA-damage-induced apoptosis p...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6603257
更新日期：2006-08-21 00:00:00
abstract：BACKGROUND:MicroRNA (miRNA)-126 (miR-126) is an endothelial-specific miRNA located within intron 7 of epidermal growth factor-like domain 7 (EGFL7). However, the role of miR-126 in cancer is controversial. METHODS:We examined the function of miR-126 in oral squamous cell carcinoma (OSCC) cells. Furthermore, a series o...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2012.330
更新日期：2012-08-07 00:00:00
abstract：BACKGROUND:The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transc...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2014.538
更新日期：2014-11-11 00:00:00
abstract：:Studies of underground miners occupationally exposed to radon have consistently demonstrated an increased risk of lung cancer in both smokers and non-smokers. Radon exposure also occurs elsewhere, especially in houses, and estimates based on the findings for miners suggest that residential radon is responsible for abo...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1998.506
更新日期：1998-08-01 00:00:00
abstract：:Fifty-one patients with advanced non-small cell lung carcinoma were treated with a combination of mitomycin C, vinblastine and cis-platin (MVP). Most cycles were given on an out-patient basis. Major side effects were leukopenia and peripheral neurotoxicity; one patient died of sepsis while leukopenic. In 44 evaluable ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1987.227
更新日期：1987-10-01 00:00:00
abstract：BACKGROUND:We studied the biological significance of genes involved in a novel t(8;12)(p21.3;p13.31) reciprocal translocation identified in cervical squamous cell carcinoma (SCC) cells. METHODS:The rearranged genes were identified by breakpoint mapping, long-range PCR and sequencing. We investigated gene expression in...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2012.301
更新日期：2012-08-07 00:00:00
abstract：:We have established a novel ascites tumour model (MDA435/LCC6) from the oestrogen receptor-negative, invasive and metastatic MDA-MB-435 human breast cancer cell line. MDA435/LCC6 cells grow as both malignant ascites and solid tumours in vivo in nude mice and nude rats, with a tumour incidence of approximately 100%. Un...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1996.29
更新日期：1996-01-01 00:00:00
abstract：:We examined the association between magnetic field (MF) exposure and survival among children with acute lymphoblastic leukaemia (ALL) treated at 51 Pediatric Oncology Group centres between 1996 and 2001. Of 1672 potentially eligible children under treatment, 482 (29%) participated and personal 24-h MF measurements wer...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6602916
更新日期：2006-01-16 00:00:00
abstract：:Tamoxifen is currently established as the endocrine treatment of choice in breast cancer. In advanced breast cancer, response rates of up to 60% in women with oestrogen receptor (ER)-positive tumours have been reported. In early breast cancer, tamoxifen can produce significant benefits, both statistically and clinical...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1998.753
更新日期：1998-09-01 00:00:00
abstract：BACKGROUND:This study aimed to evaluate the safety and efficacy of dose-dense weekly chemotherapy, followed by resection and/or thoracic radiotherapy. METHODS:Patients with histologically documented thymoma with unresectable stage III disease received 9 weeks of chemotherapy: cisplatin 25 mg m(-2) on weeks 1-9; vincri...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6605731
更新日期：2010-06-29 00:00:00
abstract：:We have investigated dihydropyrimidine dehydrogenase expression as a prognostic marker in breast cancer. A total of 119 women with breast cancer undergoing surgery between 1985 and 1996 were included in this study. Eighty-seven patients were treated with postoperative chemotherapy including 5-fluorouracil or 5-fluorou...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6600040
更新日期：2002-01-21 00:00:00
abstract：:The risk of ovarian epithelial neoplasia following use of hormonal contraceptives (HC) was examined in data from the Norwegian-Swedish Women's Lifestyle and Health cohort including 103551 women aged 30-49 years in 1991-92. Follow-up through 2000 produced 214 incident cases of histologically confirmed epithelial ovaria...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6601715
更新日期：2004-04-05 00:00:00
abstract：:A urinary gonadotrophin peptide (UGP) was isolated and purified from semi-purified human chorionic gonadotrophin (hCG), prepared from pregnancy urine. The peptide showed hCG-B subunit activity and no hCG-alpha subunit activity as demonstrated by binding studies with the relevant antibodies. It had a molecular weight s...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1988.204
更新日期：1988-09-01 00:00:00
abstract：:The effect of LiCl on melanoma cell growth and differentiation was studied in mouse and human melanoma cell lines. LiCl markedly inhibited B16 and HT-144 melanoma cell growth in vitro. Clonogenicity in soft agar of the melanoma cells was also markedly inhibited by LiCl. Pretreatment of B16 mouse melanoma cells with Li...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1987.9
更新日期：1987-01-01 00:00:00
abstract：:The influence of cyclooxygenase-2 (COX-2) overexpression on the development of tumours has been well documented. The underlying mechanism however has still not been completely elucidated. An escape of proliferating cells from the regulatory influence of TGF-beta for example in the intestine has been discussed as well ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6604048
更新日期：2007-11-19 00:00:00
abstract：:Immunoglobulins (Ig) and some complement components (C) were quantified in sera from patients with gastric carcinoma before surgery and at regular intervals during a 5-year follow-up. The preoperative concentrations of C1-INH and C4 were higher (P < 0.0005 and P < 0.005) and IgG lower (P < 0.0005) in 50 patients with ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1992.376
更新日期：1992-11-01 00:00:00
abstract：:The RNASEL gene on chromosome 1q25 has been identified as a prostate cancer susceptibility gene. We screened for RNASEL germline mutations in familial prostate cancer patients, and performed a case-control study to examine the association of specific variants with prostate cancer risk in the Japanese. Three variants w...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6601075
更新日期：2003-08-18 00:00:00
abstract：:Elderly patients are recommended to have a reduced starting dose (300 mg m(-2) once every 3 weeks) of irinotecan monotherapy. The aims of this analysis are to compare toxicity and survival according to age, performance status (PS), gender and prior radical pelvic radiotherapy (RT). The primary end points were overall ...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章,多中心研究,随机对照试验
doi：10.1038/sj.bjc.6602169
更新日期：2004-10-18 00:00:00
abstract：:Sixteen chronic myeloid leukaemia (CML) patients in remission were tested with solubilized membrane antigens from CML leukaemic cells, CML blasts, AML blasts and ALL blasts for cellular immunity in vitro by lymphocyte transformation (LT) and leucocyte migration inhibition (LMI) assays. Twelve CML patients in remission...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1979.193
更新日期：1979-09-01 00:00:00
abstract：:Human pancreatic exocrine adenocarcinoma cells established in tissue culture expressed both HLA and beta 2-microglobulin (beta 2M). Plasma-membrane components of this pancreatic cancer cell line were purified from plasma membrane fractions enriched by sucrose density-gradient centrifugation, using immunoaffinity chrom...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1979.250
更新日期：1979-11-01 00:00:00
abstract：:The influence of anthracyclines on membrane permeability functions has been investigated in HeLa cells by monitoring the efflux of fluorescein. Release of the fluorescent dye, dependent on the metabolic energy supply, occurs after the intracellular accumulation and enzymatic hydrolysis of the non-fluorescent substrate...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1986.265
更新日期：1986-12-01 00:00:00
