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To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.

•Rare and pathogenic germline variants, including in IKZF1, contribute to acute lymphoblastic leukemia in children with Down syndrome.

BackgroundThe shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline POT1mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic POT1mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of POT1mutations to development of other sporadic cancers is largely unexplored.MethodsWe performed logistic regression, adjusted for tumour mutational burden, to identify associations between POT1mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing.ResultsA total of 1834 tumours harboured a non-benign mutation of POT1(2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline POT1deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a POT1mutation (p=1.4×10−20), and 65% of POT1-mutated angiosarcoma had >1 mutations in POT1. Malignant gliomas were 1.7 times less likely to harbour a POT1mutation (p=1.2×10−3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a POT1mutation (p=0.012), while melanoma showed no differences in POT1mutation frequency versus other tumours (p=0.67).ConclusionsThese results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germline POT1deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ~50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1(odds ratio [OR], 2.02; Pmeta= 5.32 × 10−15), rs3731249 in CDKN2A(OR, 3.63; Pmeta= 3.91 × 10−10), rs7090445 in ARID5B(OR, 1.60; Pmeta= 8.44 × 10−9), and rs3781093 in GATA3(OR, 1.73; Pmeta= 2.89 × 10−8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A(OR, 1.58; Pmeta= 4.1 × 10−4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2Arisk alleles in children with DS. Finally, we investigated functional significance of the IKZF1risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2Arisk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P= .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.

It is widely suspected, yet controversial, that infection plays an etiologic role in the development of acute lymphoblastic leukemia (ALL), the most common childhood cancer and a disease with a confirmed prenatal origin in most cases. We investigated infections at diagnosis and then assessed the timing of infection at birth in children with ALL and age, gender, and ethnicity matched controls to identify potential causal initiating infections. Comprehensive untargeted virome and bacterial analyses of pretreatment bone marrow specimens (n = 127 ALL in comparison with 38 acute myeloid leukemia cases in a comparison group) revealed prevalent cytomegalovirus (CMV) infection at diagnosis in childhood ALL, demonstrating active viral transcription in leukemia blasts as well as intact virions in serum. Screening of newborn blood samples revealed a significantly higher prevalence of in utero CMV infection in ALL cases (n = 268) than healthy controls (n = 270) (odds ratio [OR], 3.71, confidence interval [CI], 1.56-7.92, P = .0016). Risk was more pronounced in Hispanics (OR=5.90, CI=1.89-25.96) than in non-Hispanic whites (OR=2.10 CI= 0.69-7.13). This is the first study to suggest that congenital CMV infection is a risk factor for childhood ALL and is more prominent in Hispanic children. Further investigation of CMV as an etiologic agent for ALL is warranted.

ABSTRACTEpigenome-wide DNA methylation association studies have identified highly replicable genomic loci sensitive to maternal smoking during gestation. The role of inter-individual genetic variation in influencing DNA methylation, leading to the possibility of confounding or bias of such associations, has not been assessed. We investigated whether the DNA methylation levels at the top 10 CpG sites previously associated with exposure to maternal smoking during gestation were associated with individual genetic variation at the genome-wide level. Genome-wide association tests between DNA methylation at the top 10 candidate CpG and genome-wide SNPs were performed in 736 case and control participants of the California Childhood Leukemia Study. Three of the strongest maternal-smoking sensitive CpG sites in newborns were significantly associated with SNPs located proximal to each gene: cg18146737in the GFI1gene with rs141819830(P= 8.2×10−44), cg05575921in the AHRRgene with rs148405299(P= 5.3×10−10), and cg12803068in the MYO1Ggene with rs61087368(P= 1.3×10−18). For the GFI1CpG cg18146737, the underlying genetic variation at rs141819830confounded the association between maternal smoking and DNA methylation in our data (the regression coefficient changed from −0.02 [P= 0.139] to −0.03 [P= 0.015] after including the genotype). Our results suggest that further studies using DNA methylation at cg18146737, cg05575921, or cg12803068that aim to assess exposure to maternal smoking during gestation should include genotype at the corresponding SNP. New methods are required for adequate and routine inclusion of genotypic influence on DNA methylation in epigenome-wide association studies to control for potential confounding.

Killer cell immunoglobulin-like receptors (KIRs), via interaction with their cognate HLA class I ligands, play a crucial role in the development and activity of natural killer cells. Following recent reports of KIR gene associations in childhood acute lymphoblastic leukemia (ALL), we present a more in-depth investigation of KIR genes and their cognate HLA ligands on childhood ALL risk. Genotyping of 16 KIR genes, along with HLA class I groups C1/C2 and Bw4 supertype ligands, was carried out in 212 childhood ALL cases and 231 healthy controls. Frequencies of KIR genes, KIR haplotypes, and combinations of KIR-HLA ligands were tested for disease association using logistic regression analyses. KIR A/A genotype frequency was significantly increased in cases (33.5%) compared with controls (24.2%) (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.04-2.39). Stratifying analysis by ethnicity, a significant difference in KIR genotype frequency was demonstrated in Hispanic cases (34.2%) compared with controls (21.9%) (OR = 1.86; 95% CI, 1.05-3.31). Homozygosity for the HLA-Bw4 allele was strongly associated with increased ALL risk exclusively in non-Hispanic white children (OR = 3.93; 95% CI, 1.44-12.64). Our findings suggest a role for KIR genes and their HLA ligands in childhood ALL etiology that may vary among ethnic groups.

Killer cell immunoglobulin-like receptors (KIRs), via interaction with their cognate HLA class I ligands, play a crucial role in the development and activity of natural killer cells. Following recent reports of KIRgene associations in childhood acute lymphoblastic leukemia (ALL), we present a more in-depth investigation of KIRgenes and their cognate HLAligands on childhood ALL risk. Genotyping of 16 KIRgenes, along with HLAclass I groups C1/C2 and Bw4 supertype ligands, was carried out in 212 childhood ALL cases and 231 healthy controls. Frequencies of KIRgenes, KIRhaplotypes, and combinations of KIR-HLAligands were tested for disease association using logistic regression analyses. KIRA/A genotype frequency was significantly increased in cases (33.5%) compared with controls (24.2%) (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.04-2.39). Stratifying analysis by ethnicity, a significant difference in KIRgenotype frequency was demonstrated in Hispanic cases (34.2%) compared with controls (21.9%) (OR = 1.86; 95% CI, 1.05-3.31). Homozygosity for the HLA-Bw4allele was strongly associated with increased ALL risk exclusively in non-Hispanic white children (OR = 3.93; 95% CI, 1.44-12.64). Our findings suggest a role for KIRgenes and their HLAligands in childhood ALL etiology that may vary among ethnic groups.

Purpose: Autism is one of the most heritable complex disorders, but the genetic etiology of autism spectrum disorders is unexplained in ~90% of cases. Highly penetrant microdeletions and microduplications of 16p11.2 contribute to the pathogenesis of autism spectrum disorder, but the extent to which these variants account for the total burden of idiopathic autism spectrum disorders has not been systematically investigated.Methods: A systematic literature review and meta-analysis were performed to determine the prevalence of these variants among individuals diagnosed with autism spectrum disorders. A planned subgroup analysis was conducted to assess prevalence differences between sporadic and familial autism spectrum disorder cases.Results: In the combined analysis of 3613 idiopathic autism spectrum disorder cases from seven studies, the meta-analytic prevalence of these microdeletions and microduplications was 0.76% (95% CI, 0.51–1.12%). When stratified by copy number variant-type, the prevalence of microdeletions was 0.50% (95% CI, 0.31–0.82%) and the prevalence of microduplications was 0.28% (95% CI, 0.14–0.56%). Sporadic autism spectrum disorder cases showed only a slightly higher prevalence than familial cases.Conclusion: The number needed to test to identify one such variant is 132 patients (95% CI, 89–198). Such information, especially as it pertains to diagnostic yield in genetic testing, should prove useful to clinicians considering chromosomal microarray analysis in subjects with autism spectrum disorders.

Autism is one of the most heritable complex disorders, but the genetic etiology of autism spectrum disorders is unexplained in ~90% of cases. Highly penetrant microdeletions and microduplications of 16p11.2 contribute to the pathogenesis of autism spectrum disorder, but the extent to which these variants account for the total burden of idiopathic autism spectrum disorders has not been systematically investigated.

Asthma is a chronic inflammatory disease of the lungs which affects more than 6.5 million American children. A family-based genome-wide association study of copy-number variation identified an association between decreased copy-number at TCRγand childhood allergic asthma. TCRγencodes the T-cell receptor gamma glycoprotein, a cell-surface protein found on T-cells and involved in cell-mediated immunity. Using quantitative real-time PCR, we sought to determine if copy-number variation at TCRα, TCRβor TCRγwas associated with childhood allergic asthma in an independent cohort of 94 cases and 455 controls using DNA from buccal swabs. Copy-number variation at these loci is well-known, but appears to be dominated by somatic mutations. Genotyping results indicated that copy-number variants at these genes are largely somatic mutations, as inheritance did not show Mendelian consistency. In these mosaic cell populations, copy-number was significantly reduced among asthmatic children at TCRγ(p=0.0199), but was not associated at TCRαor TCRβ(p=0.7972 and 0.8585, respectively). These findings support the association between reduced copy-number at TCRγand childhood allergic asthma. Further work is needed to resolve whether reduced copy-number at TCRγpredisposes individuals to asthma, or whether deletion of this gene is a somatic response to the disease.

No relevant conflicts of interest to declare.

Recent studies using next-generation sequencing of selected individuals, such as those with familial leukemia or congenital syndromes, have identified rare and highly penetrant germline mutations that predispose to childhood acute lymphoblastic leukemia (ALL). High hyperdiploidy (HD), the most common cytogenetic subtype of childhood ALL, is enriched in children with RASopathies who develop ALL and, similarly, a high proportion of ALL patients with germline ETV6or IKZF1mutations presented with the HD subtype. Here, we aimed to identify novel predisposition genes in a selected group of HD-ALL patients.

Genome-wide association studies (GWAS) have revealed heritable genetic risk factors for childhood acute lymphoblastic leukemia (ALL), highlighting the role of lymphoid development and cell cycle control genes in disease etiology. Most studies have focused on non-Latino white populations; however, the highest global rates of ALL are found in Latinos in the US and Latin America. To identify novel genetic susceptibility alleles, we carried out a large, multi-ethnic GWAS of ALL in the Californian population.

No relevant conflicts of interest to declare.

During the past six years, researchers have made major progress identifying common inherited genetic variation that increases risk for primary adult glioma. This paper summarizes knowledge about rare familial cancer syndromes that include adult glioma and reviews the available literature on the more recently discovered common inherited variation. Ten independent inherited variants in eight chromosomal regions have been convincingly associated with increased risk for adult glioma. Most of these variants increase relative risk of primary adult glioma by 20% to 40%, but the TP53 variant rs78378222 confers a two-fold relative risk (ie, 200%), and rs557505857 on chromosome 8 confers a six-fold relative risk of IDH-mutated astrocytomas and oligodendroglial tumors (ie, 600%). Even with a six-fold relative risk, the overall risk of developing adult glioma is too low for screening for the high-risk variant on chromosome 8. Future studies will help clarify which inherited adult glioma risk variants are associated with subtypes defined by histology and/or acquired tumor mutations. This review also provides an information sheet for primary adult glioma patients and their families.

High hyperdiploidy (HD), the most common cytogenetic subtype of acute lymphoblastic leukemia (ALL), is characterized by a nonrandom gain of chromosomes and is thought to arise from a single abnormal mitosis. However, the causes of this leukemia-initiating event remain unknown. A recognized enrichment of HD-ALL among children with RASopathies and with germline ETV6mutations suggests that germline predisposition underlies a component of HD-ALL risk, in addition to the increased risk of the HD subtype with ALL-associated heritable risk variants in PIP4K2A, ARID5B, and CEBPE. Though cure rates of HD-ALL are high, the significant treatment-related morbidities and mortality warrant more etiologic investigations which may reveal molecularly-targeted therapies for this disease.

Lower-grade (World Health Organization Grades II and III) gliomas vary widely in clinical behavior and are classified as astrocytic, oligodendroglial, or mixed. Anaplasia depends greatly on mitotic activity, with CDKN2A loss considered as the most common mechanism for cell cycle dysregulation. We investigated whether loss of the CDKN2A gene is associated with overall survival across pathologically and genetically defined glioma subtypes. After adjustment for IDH mutation, sex, and age, CDKN2A deletion was strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas or oligoastrocytomas. Molecular classification of astrocytomas by IDH mutation, TP53 mutation, and /or ATRX loss of expression revealed that CDKN2A loss in IDH/TP53 mutated tumors was strongly associated with worse overall survival. CDKN2A loss in IDH mutated tumors with ATRX loss was only weakly associated with worse overall survival. These findings suggest that CDKN2A testing may provide further clinical aid in lower-grade glioma substratification beyond IDH mutation and 1p19q codeletion status, particularly in IDH/TP53 mutated astrocytomas.

No relevant conflicts of interest to declare.

Little is known about the interaction between constitutive and somatic genetic variation in carcinogenesis. Genome-wide association studies (GWAS) of childhood acute lymphoblastic leukemia (ALL) have identified 6 genetic associations, including the single nucleotide polymorphism (SNP) rs3731217, located between the CDKN2Aand CDKN2Bgenes. Somatic deletions of this chromosome 9p21.3 region are common in cancer, and occur in ~30% of childhood ALL.

Purpose: We sought to identify and characterize the functional polymorphism in the CCAAT/enhancer binding protein (C/EBP), epsilon (CEBPE)gene, which is known to harbor a genetic risk modifier for childhood acute lymphoblastic leukemia (ALL).

No relevant conflicts of interest to declare.