RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia.

Activating mutations in the RAS oncogenes are among the most common genetic alterations in human cancers, including patients with acute lymphoblastic leukemia (ALL). We sought to define the frequency and spectrum, and possible prognostic importance, of N- and K-RAS mutations in children with ALL treated with contemporary therapy. Leukemic blast DNA from 870 children was analyzed for the presence of activating mutations in the N- or K-RAS oncogenes using a sensitive mutation detection algorithm. RAS mutations were present in the blasts of 131 (15.1%) pediatric ALL patients. The spectrum of mutations included 81 (9.3%) mutations of codons 12/13 of N-RAS, 12 (1.4%) mutations of codon 61 of N-RAS, 39 (4.5%) mutations of codons 12/13 of K-RAS, and 2 (0.2%) mutations of codon 61 of K-RAS. The presence of N- or K-RAS mutations was not associated with white blood cell count at diagnosis, sex, race, extramedullary testicular involvement, central nervous system disease, or NCI/CTEP ALL Risk Group. Patients with an exon 1 K-RAS mutation (codons 12/13) were significantly younger at diagnosis (P=0.001) and less frequently B-lineage phenotype (P=0.01). RAS mutation status did not predict overall survival, event-free survival and disease-free survival. While N- and K-RAS mutations can be identified in 15% of children with newly diagnosed ALL, they do not represent a significant risk factor for outcome using contemporary chemotherapy regimens.     

Favorable prognosis associated with hyperdiploidy in children with acute lymphocytic leukemia correlates with extra chromosome 6. A Pediatric Oncology Group study

Pretreatment bone marrow cytogenetic studies were included for 1664 patients with acute lymphoblastic leukemia (ALL) accrued to Pediatric Oncology Group (POG) 8035 laboratory classification study from May 1981 through January 1986. There was a significant difference (P = 0.0001) in distribution of stem-line karyotype (normal, hypodiploid, pseudodiploid, or hyperdiploid) among children with early pre-B, pre-B, or T-cell ALL, with early pre-B patients demonstrating a higher proportion of hyperdiploid karyotypes with modal chromosome numbers greater than 51. Cytogenetic classification of 1216 patients with early pre-B or pre-B ALL evaluable for duration of event-free survival (EFS), with median follow-up of 42 months, showed a significant prolongation of five-year EFS associated with hyperdiploidy greater than 51 (75%; standard error [SE] = 5%) compared with hyperdiploidy 47 to 51 (46%; SE = 7%), hypodiploidy (55%; SE = 11%), and pseudodiploidy (45%; SE = 7%) (P = 0.0001). Five-year EFS was intermediate for patients with normal (58%), constitutionally abnormal (66%), or unsuccessful analyses (66%). The breakpoint defining hyperdiploidy associated with better prognosis was best defined as greater than 51 (P = 0.0002). Of 239 children with hyperdiploid karyotypes, analysis of the contribution of each chromosome to EFS duration showed a significant association between improved EFS and additional chromosome(s) six (P = 0.02). Chromosome translocation was associated with shorter EFS (P = 0.0001).     

RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML).

Juvenile myelomonocytic leukemia (JMML) is a malignant hematopoietic disorder of early childhood with excessive proliferation of the myeloid and monocytic lineage. Deregulation of the RAS signal transduction pathway is thought to play a key role in its pathogenesis. We examined peripheral blood or bone marrow cells of 36 children with JMML for activating point mutations in codons 12, 13 and 61 of the NRAS and KRAS proto-oncogenes by allele-specific restriction assay, single-strand conformation polymorphism and/or direct sequencing. Codons 12, 13 and 61 of HRAS were examined in 26 of these patients. We detected RAS mutations in six cases (17%) located at N12 (n = 2), N13 (n = 3) and K13 (n = 1). In addition, we performed clonality studies on different cell lineages in four of these patients applying the RAS mutation, the karyotype and X-chromosome inactivation patterns as clonal markers. Erythroid cells carried mutant RAS, indicating clonal origin. In EBV B cell lines, one of three patients studied harbored a RAS mutation, while the other two patients had polyclonal B cells with wild-type RAS. T lymphocytes were examined in one patient; they were polyclonal and had wild-type RAS. It is likely that JMML is a heterogeneous disease with respect to clonal involvement of different lineages.     

A population-based case-control study of childhood leukemia in Shanghai

A population-based case-control interview study of 309 childhood leukemia cases and 618 healthy population control children was conducted in urban Shanghai, China. Like some studies in other countries, excess risks for both acute lymphocytic leukemia (ALL) and acute nonlymphocytic leukemia (ANLL) were associated with intrauterine and paternal preconception diagnostic x-ray exposure, and with maternal employment in the chemical and agricultural industries during pregnancy. ANLL was linked to maternal occupational exposure to benzene during pregnancy, whereas both ALL and ANLL were significantly associated with maternal exposure to gasoline and the patient's prior use of chloramphenicol. New findings, previously unsuspected, included an association of ANLL with younger maternal age at menarche (odds ratio [OR] = 4.3; 95% confidence interval (CI) = 1.3-13.9); a protective effect for long-term (greater than 1 year) use of cod liver oil containing vitamins A and D for both ALL (OR = 0.4; 95% CI = 0.2-0.9) and ANLL (OR = 0.3; 95% CI = 0.1-1.0); and excess risks of ANLL among children whose mothers were employed in metal refining and processing (OR = 4.6; 95% CI = 1.3-17.2) and of ALL associated with maternal occupational exposure to pesticides (OR = 3.5; 95% CI = 1.1-11.2). No relationships were found with late maternal age, certain congenital disorders, or familial occurrence, which have been related to childhood leukemia in other studies. In contrast with other reports, an excess of leukemia, primarily ANLL, occurred among second or later-born rather than firstborn children.     

Correlation of karyotype and immunophenotype in childhood acute lymphoblastic leukemia

To correlate leukemic cell karyotype with immunophenotype, we studied 364 children with acute lymphoblastic leukemia (ALL). A prognostically favorable cytogenetic feature, hyperdiploidy greater than 50 chromosomes, was found in 33% of cases classified as common ALL antigen positive (CALLA+) early pre-B (common) ALL, in contrast to 18% of pre-B cases (P = .012), 5% of T cell cases (P less than .001), and none of the B cell cases (P less than .001) or cases of CALLA negative (CALLA-) early pre-B ALL (P = .002). The frequency of translocations, an adverse cytogenetic feature, was significantly lower in CALLA+ early pre-B ALL cases (35%) than in B cell (100%; P less than .0001), pre-B (59%; P less than .001), or CALLA- early pre-B (62%; P = .016) cases. Thus, patterns of chromosomal change differ widely among the major immunophenotypic groups of ALL and may account for reported differences in responsiveness to treatment.     

EGFR基因突变与非小细胞肺癌临床病理特征的关系

目的 研究临床病理特征及相关实验室检测指标与非小细胞肺癌患者外科手术治疗预后的关系.方法手术切除的非小细胞肺癌患者标本一共190例,采用实时荧光PCR法,检测EGFR 基因第 18、19、20 和 21 号外显子的突变情况.分析EGFR基因突变与其临床病理关系、EGFR基因突变丰度和临床特征的关系.结果 EGFR基因突变的影响因素包括:性别、吸烟史、病理分型,高危因素包括:女性、吸烟者、腺癌.190例 NSCLC 患者肿瘤组织中,成功检测出90例存在 EGFR 基因突变,EGFR 突变丰度与性别(P=0.962)、吸烟史(P=0.809)无相关性;EGFR突变丰度与病理分型相关.和非腺癌对比,腺癌患者EGFR基因突变丰度明显更高,(x2=14.110,P=0.000).术前腺癌血清VEGF水平明显低于非腺癌组,P＜0.05;术后腺癌血清CD44v6明显高于非腺癌患者,P＜0.05;术后Ⅲ～Ⅳ期组血清VEGF、CD44v6水平明显高于Ⅰ～Ⅱ期患者,P＜0.05.结论 非小细胞肺癌EGFR基因突变的高危因素为吸烟者、女性、腺癌,与年龄、性别、肿瘤分期、吸烟史无明显相关性.     

Gestational and familial risk factors for childhood astrocytoma: results of a case-control study

Gestational and familial risk factors were investigated for their association with astrocytoma, the most frequently occurring brain tumor in children. A case-control study of 163 matched pairs was performed. Cases under 15 years of age at diagnosis in 1980-1986 were identified through the tumor registries of 8 hospitals in Pennsylvania, New Jersey, and Delaware. Controls were selected by random digit dialing and were matched to cases for age, race, and telephone area code and exchange. Maternal antinausea medications increased the risk of childhood astrocytoma [OR (odds ratio) = 2.0, P = 0.04]. Cured meat consumption during pregnancy was more common among cases (OR = 1.9, P = 0.07), and a significant trend with increasing frequency of consumption was observed (P = 0.04). Results for gestational exposure to marijuana (OR = 2.8, P = 0.07) were of borderline significance. Gestational exposure to neurally active medications, alcohol, and tobacco were not risk factors. There was a significant trend for cases to be of higher birth weight (P = 0.03). Mental retardation (OR = 3.0, P = 0.04) and cancer (OR = 1.7, P = 0.02) in a relative of the child significantly increased the risk of astrocytoma. Significantly increased risks were observed for brain tumors in relatives of children 0-4 years of age at diagnosis (OR = 6/0, P = 0.04). A significant protective effect was observed for maternal history of miscarriage or stillbirth (OR = 0.5, P = 0.01). The results of this study suggest that some gestational and familial factors may increase the risk of childhood astrocytoma.     

RAS Pathway Mutation Patterns in Patients With Juvenile Myelomonocytic Leukemia: A Developing Country Single-center Experience

IntroductionJuvenile myelomonocytic leukemia (JMML) is a rare clonal myelodysplastic/myeloproliferative neoplasm of early childhood. Historically, it was difficult to diagnose clinically, as patients present with manifestations shared with other hematologic malignancies or viral infections. It is now clear that JMML is a disease of hyperactive RAS signaling.Patients and MethodsWe examined the bone marrow of 41 Egyptian children with JMML by direct sequencing for mutations in the RAS pathway genes.ResultsMutations were detected in 33 (80%) of 41 patients. We identified 12 (29%) of 41 patients with PTPN11 mutation; 18 (44%) of 41 with RAS mutation; 9 (22%) of 41 with NRAS mutation; 9 (22%) of 41 with KRAS mutation; and 3 (7%) of 41 with CBL mutation. Eleven (92%) of the PTPN11 mutations were detected in exon 3 and 1 (8%) in exon 13. Seven of the NRAS mutations were in exon 2, and 2 were in exon 3. All KRAS mutations were in exon 2. The 3 cases with CBL mutation were homozygous mutations in exon 8. All the mutations detected in PTPN11, NRAS/KRAS, and the CBL genes were previously reported missense mutations in JMML.ConclusionOur results demonstrate that Egyptian children diagnosed with JMML have high frequency of NRAS/KRAS mutations and lower frequency of PTPN11 mutations as compared with previous studies. The concept of mutually exclusive RAS pathway mutations was clearly observed in our patients. All cancer centers in our region should start implementing molecular diagnostic methods before confirming the diagnosis of JMML and before offering hematopoietic stem cell transplantation.     

Frequency of <Emphasis Type="Italic">FLT3</Emphasis> mutations in childhood acute lymphoblastic leukemia

FLT3 mutations are occasionally observed in acute lymphoblastic leukemia (ALL). These most frequently manifest as internal tandem duplications (ITD) and activation loop (AL) mutations. This study investigated the incidence of FLT3 mutations in 86 pediatric patients diagnosed with ALL and the co-presence of common RAS mutations. A 2.3% (2/86) FLT3/AL mutation rate in terms of total ALL cases and a 22% (2/9) incidence in hyperdiploid cases was observed. This is in accordance to previous studies indicating a higher incidence in the patient subgroup associated with hyperdiploidy.     

Childhood cancer and parental use of tobacco: findings from the inter-regional epidemiological study of childhood cancer (IRESCC)

Parental smoking data have been re-abstracted from the interview records of the Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC) to test further the hypothesis that paternal cigarette smoking is a risk factor for the generality of childhood cancer. Reported cigarette smoking habits for the parents of 555 children diagnosed with cancer in the period 1980-1983 were compared, in two separate matched pairs analyses, with similar information for the parents of 555 children selected from GP lists (GP controls) and for the parents of 555 hospitalized children (hospital controls). When cases were compared with GP controls there was a statistically significant positive trend (P = 0.02) between the risk of childhood cancer and paternal daily consumption of cigarettes before the pregnancy; there was no significant trend for maternal smoking habit. When cases were compared with hospital controls there was a statistically significant negative trend (P< 0.001) between the risk of childhood cancer and maternal daily consumption of cigarettes before the pregnancy; there was no significant trend for paternal smoking habit. Neither of the significant trends could be explained by adjustment for socioeconomic grouping, ethnic origin or parental age at the birth of the child, or by simultaneous analysis of parental smoking habits. Relations between maternal consumption of cigarettes and birth weights suggested that (maternal) smoking data were equally reliable for case and control subjects, although comparisons with national data suggested that the hospital control parents were unusually heavy smokers. These findings give some support for the hypothesis that paternal cigarette smoking is a potential risk factor for the generality of childhood cancers.     

Reproductive history, infertility treatment, and the risk of acute leukemia in children with down syndrome: a report from the Children's Oncology Group

BACKGROUND: Children with Down syndrome (DS) have from 10 to 20 times the risk of developing acute leukemia than the general pediatric population. There is mixed evidence for associations between reproductive history or infertility and acute leukemia among children without DS. METHODS: The authors conducted a case-control study of acute leukemia among children with DS to investigate possible risk factors in this population. From 1997 to 2002, 158 children aged <20 years with DS who had a diagnosis of acute leukemia (97 children with acute lymphoblastic leukemia [ALL] and 61 children with acute myeloid leukemia [AML]) were enrolled at Children's Oncology Group (COG) institutions. Controls with DS (n = 173) were selected from the cases' primary care clinic and frequency matched to cases on age. Telephone interviews were conducted with mothers of cases and controls assessing reproductive history, infertility, and infertility treatment. RESULTS: Null results were observed overall and by subtype for reproductive factors, including previous pregnancy outcomes and contraceptive use, and for most infertility outcomes. There was an increased risk of AML among children with DS whose parents had ever tried for >/=1 year to become pregnant (odds ratio [OR], 2.22; 95% confidence interval [95% CI], 1.14-4.33). A 1-year increase in maternal age also was associated with AML (OR, 1.06; 95% CI, 1.01-1.12). CONCLUSIONS: Although the questionnaire was limited in this area, the results suggested that the risk for AML may be raised in children with DS because of infertility. In that the risk of infertility, along with having a child with DS, increase with age, these results warrant more research.     

PTPN11, RAS and FLT3 mutations in childhood acute lymphoblastic leukemia

PTPN11, the gene which encodes protein tyrosine phosphatase SHP-2, plays an important role in regulating intracellular signaling. Germline mutations in PTPN11 were first observed in Noonan syndrome, while somatic mutations were identified in hematological myeloid malignancies. Recently, PTPN11 mutations have been reported in children with acute lymphoblastic leukemia (ALL). In the present study, we investigated the prevalence of mutations in PTPN11, RAS and FLT3 in samples from 95 Japanese children with ALL. We observed exon 3 and 8 missense mutations of PTPN11 in 6 children with B precursor ALL. One patient with Down syndrome and ALL had PTPN11 mutation. We also identified RAS mutations in ten patients and FLT3 internal tandem duplication (FLT3/ITD) in one patient. None of the patients had simultaneous mutations in PTPN11 and RAS, while one patient had both PTPN11 and FLT3 mutations. These data suggest that PTPN11 mutation may play an important role for leukemogenesis in a proportion of children with ALL, particularly B precursor ALL.     

Paternal smoking, genetic polymorphisms in CYP1A1 and childhood leukemia risk

We conducted a case-control study to evaluate the association between paternal smoking and childhood leukemia and to evaluate potential modification by polymorphisms in CYP1A1. Histologically confirmed childhood leukemia cases (n=164) and non-cancer controls (n=164) were recruited from three teaching hospitals in Seoul, Korea. Five single nucleotide polymorphisms in CYP1A1 (-17961T>C, -9893G>A, I462V, 1188C>T (*2A), and 11599C>G) were genotyped and haplotypes were estimated by the expectation-maximization method. We also conducted a meta-analysis of 12 studies that have reported the association between paternal smoking and childhood leukemia risk. Paternal smoking at home was associated with all leukemias (OR=1.8, 95% CI=1.1-2.8) and acute lymphoblastic leukemia (ALL) (2.0, 1.2-3.4). An increasing trend in risk was observed for pack-years smoked after birth (P(trend)=0.06 and 0.02, respectively) and the number of smokers in the home during the child's life (P(trend)=0.05 and 0.03, respectively). Among those without the CGACC haplotype, ALL risk was significantly increased by the father's smoking at home (2.8, 1.5-5.3) and the presence of at least one smoker in the home (2.3, 1.2-4.4), and the test for interaction was significant (P(interaction)=0.03 and 0.02, respectively). The meta-analysis showed that overall paternal smoking (1.13, 1.04-1.24) and smoking before the pregnancy of the child (1.12, 1.04-1.21) were significantly associated with childhood leukemia risk. Our results suggest that paternal smoking is a risk factor for childhood leukemia and the effect may be modified by CYP1A1 genotype.     

NSCLC EGFR突变与吸烟的交互作用及其与miR-221表达的相关性

目的:分析NSCLC EGFR突变与吸烟等因素的交互作用,及其与miR-221表达的相关性,为肺癌分子机制研究提供线索和依据。方法:采用高分辨熔解曲线法（high resolution melting,HRM）进行EGFR突变检测,以EGFR突变阳性为病例组,野生型为对照组,logistic回归分析EGFR突变与吸烟等因素在肺癌中的交互作用,Spearman分析EGFR突变与miR-221表达的相关性。结果:吸烟者相对于不吸烟者,EGFR突变差异具有统计学意义（P=0.034）,不吸烟者EGFR突变率较高。性别、年龄、饮酒、组织学类型、肿瘤直径、TNM分期、分化程度、肿瘤家族史以及心脑血管疾病史与EGFR突变无统计学关系（P＞0.05）;NSCLC EGFR突变与吸烟、饮酒、肿瘤家族史以及心脑血管疾病史对肺癌的发生不存在相乘交互作用;miR-221表达在NSCLC组织明显高于非癌肺组织,差异有统计学意义（P=0.017）;EGFR突变与miR-221表达无相关性（r=-0.034,P=0.858）。结论:NSCLC EGFR突变与吸烟、饮酒、肿瘤家族史及心脑血管疾病史均不存在相乘交互作用,miR-221表达在NSCLC组织中高于非癌病人肺组织,与EGFR突变无相关性。     

Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma

PURPOSE: KRAS mutations are found in approximately 25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib. EXPERIMENTAL DESIGN: We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas. RESULTS: KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G-->A) rather than the transversion mutations known to be smoking-related (G-->T or G-->C; P < 0.0001). CONCLUSIONS: Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.     

TET2合并DNMT3A突变及其他共存基因突变对急性髓系白血病患者预后的影响

  目的  探究TET2合并DNMT3A突变及其他共存基因突变对成人非M3型急性髓系白血病（acute myeloid leukemia,AML）患者预后的影响。  方法  回顾性分析2018年1月至2021年9月于南昌大学第一附属医院确诊的初治且行血液肿瘤相关突变基因外显子二代测序检测的512例成人 AML（非 M3 型）患者的临床资料,分析患者的临床特征、疗效及生存情况。  结果  本研究共纳入110例AML患者,TET2突变组64例,DNMT3A单突变组46例。男性50例（45.5%）,中位年龄54（15～79）岁。TET2基因突变频率为12.5%（64/512）,98.4%（63/64）患者突变基因数≥2个,每例患者平均合并5.2个突变基因。NPM1（43.8%）、DNMT3A（42.2%）、FLT3-ITD/TKD（40.6%）、CEBPA（26.6%）、TTN（20.3%）为TET2突变常见的共存突变基因。TET2合并DNMT3A突变患者初次诱导完全缓解（complete response,CR）率为46.2%,略低于TET2单突变患者的76.9%（P=0.077）,与DNMT3A单突变患者无显著性差异（P=0.952）。TET2合并DNMT3A突变患者的中位总生存（median overall survival,mOS）时间为9.5个月,明显低于TET2单突变患者（P=0.002）,而与DNMT3A单突变患者无显著性差异（P=0.414）。三者的中位无复发生存（median relapse- free survival,mRFS）时间无显著性差异（P>0.05）。在TET2突变背景下,合并K/NRAS突变患者的CR率为28.6%,明显低于无K/NRAS突变患者的75.0%（P=0.030）,合并FLT3-ITD突变患者的mOS明显短于无FLT3-ITD突变患者（P=0.030）。多因素分析显示年龄≥60岁、合并FLT3-ITD突变、初次诱导未达CR是影响TET2突变AML患者总生存时间（overall survival,OS）的独立危险因素,DNMT3A突变不影响TET2突变患者OS。  结论  TET2突变是AML患者常见突变,且常合并共存基因突变。共存基因突变与TET2突变共同影响AML患者预后。基于二代测序的基因突变检测对指导AML精确分层及精准治疗具有重要意义。      

Maternal coffee and alcohol consumption during pregnancy, parental smoking and risk of childhood acute leukaemia

INTRODUCTION: We investigated the role of maternal alcohol and coffee drinking and parental smoking on the risk of childhood acute leukemia in a multicenter case-control study. METHODS: The study included 280 incident cases and 288 hospitalized controls, frequency matched with the cases by age, gender and center. Data collection was completed by face-to-face standardized interviews of the case and control mothers. RESULTS: An association with maternal alcohol consumption during pregnancy was observed with acute lymphoid leukemia (ALL) (OR=2.0 [1.4-3.0]) and acute non-lymphoid leukemia (ANLL) (OR=2.6 [1.2-5.8]). Maternal coffee consumption during pregnancy was associated with childhood acute leukemia, ORs increasing in ALL with coffee consumption (OR=1.1 [0.7-1.8], OR=2.4 [1.3-4.7] and OR=3.1 [1.0-9.5], respectively, for < or =3, 4-8 and >8 cups/day). No association with maternal smoking during pregnancy or parental smoking before or after the index child's birth was observed. DISCUSSION: Our results suggest an association with maternal alcohol and coffee drinking during pregnancy and call for further investigations. Besides, the present study does not support the hypothesis of an increase in the risk of childhood leukemia related to parental smoking.     

Parental smoking and childhood cancer: results from the United Kingdom Childhood Cancer Study

There are strong a priori reasons for considering parental smoking behaviour as a risk factor for childhood cancer but case - control studies have found relative risks of mostly only just above one. To investigate this further, self-reported smoking habits in parents of 3838 children with cancer and 7629 control children included in the United Kingdom Childhood Cancer Study (UKCCS) were analysed. Separate analyses were performed for four major groups (leukaemia, lymphoma, central nervous system tumours and other solid tumours) and more detailed diagnostic subgroups by logistic regression. In the four major groups, after adjustment for parental age and deprivation there were nonsignificant trends of increasing risk with number of cigarettes smoked for paternal preconception smoking and nonsignificant trends of decreasing risk for maternal preconception smoking (all P-values for trend >0.05). Among the diagnostic subgroups, a statistically significant increased risk of developing hepatoblastoma was found in children whose mothers smoked preconceptionally (OR=2.68, P=0.02) and strongest (relative to neither parent smoking) for both parents smoking (OR=4.74, P=0.003). This could be a chance result arising from multiple subgroup analysis. Statistically significant negative trends were found for maternal smoking during pregnancy for all diagnoses together (P<0.001) and for most individual groups, but there was evidence of under-reporting of smoking by case mothers. In conclusion, the UKCCS does not provide significant evidence that parental smoking is a risk factor for any of the major groups of childhood cancers.