A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution

Abstract

Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case-control population (Ncases=1464, Ncontrols=3279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European-ancestry (OR=2.99; P=1.51×10−9) and Hispanic children (OR=2.77; P=3.78×10−4). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial=0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS “hits” and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors.

Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case–Control and Family-Based Studies in Multiethnic Populations

“…ARID5B, IKZF1 , CDKN2A/2B and PIP4K2A all contain SNPs associated with ALL at a genome-wide significant level in previous GWA and expression studies (8–13). We then tested for replication of the 42 resulting gene hits ( p < 10 −3 , Bonferroni-corrected for the number of haplotype blocks in the genome (38)) using a replication dataset of gene-level p -values calculated from a second dataset of case-control GWA p -values (14) (Table 1 and Supplemental Table S3).…”

Applicability of digital PCR to the investigation of pediatric-onset genetic disorders

“…SMART-ddPCR uses a similar strategy to RMD and RHDO (Section 2.2). This approach has identified subclonal somatic CNVs using SNPs within CDKN2A ( cyclin-dependent kinase inhibitor 2A ) and IKZF1 ( Ikaros ) in ALL patients [56] and found ALL-associated PAI of the CDKN2A(A148T) risk allele [57]. The CDKN2A and IKZF1 copy numbers measured with SMART-ddPCR were in agreement with those measured by multiplex ligation-dependent probe amplification (MLPA) [56].…”

“…Tumor PAI can be detected by Sanger sequencing and SNP genotyping but neither technique is quantitative. The somatic mutation allelic ratio test using digital droplet PCR (SMART-ddPCR) quantifies PAI in ALL tumor DNA [56], [57]. SMART-ddPCR uses a similar strategy to RMD and RHDO (Section 2.2).…”

Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors

“…The 9p21.3 locus in general, and the CDKN2A/CDKN2B genes in specific, are a classic examples of pleiotropic regions since they are associated with a very large number of human traits and diseases171819222324. Pleiotropic regions are probably more accessible DNA stretches than normal and therefore variability within them may result to be non neutral more likely than in any other randomly selected DNA sequence.…”

“…Genetic polymorphisms in the locus have been reported to be associated with type two diabetes mellitus (T2DM), which is a one of the few suggested risk factors for PNETs141516, suggesting a shared genetic background between T2DM and PNETs. Genetic variants belonging to the CDKN2A/2B region have been identified through GWAS as susceptibility markers for several human traits and diseases, including a large number of tumor types1718192021222324. In addition we have recently showed the association of the CDKN2A/2B -rs3217992 SNP with increased risk of pancreatic ductal adenoma carcinoma (PDAC)25.…”