Confirmation of involvement of new variants at CDKN2A/B in pediatric acute lymphoblastic leukemia susceptibility in the Spanish population

Abstract

The locus CDKN2A/B (9p21.3), which comprises the tumor suppressors genes CDKN2A and CDKN2B and the long noncoding RNA (lncRNA) known as ANRIL (or CDKN2B-AS), was associated with childhood acute lymphoblastic leukemia (ALL) susceptibility in several genome wide association studies (GWAS). However, the variants associated in the diverse studies were different. Recently, new and independent SNPs deregulating the locus function were also identified in association with ALL risk. This diversity in the results may be explained because different variants in each population could alter CDKN2A/B locus function through diverse mechanisms. Therefore, the aim of this study was to determine whether the annotated risk variants in the CDKN2A/B locus affect the susceptibility of B cell precursor ALL (B-ALL) in our Spanish population and explore if other SNPs altering additional regulatory mechanisms could be also involved. We analyzed the four SNPs proposed by GWAs and two additional SNPs in miRNA binding sites in 217 pediatric patients with B-ALL and 330 healthy controls. The SNPs rs2811712, rs3731249, rs3217992 and rs2811709 were associated with B-ALL susceptibility in our Spanish population. ALL subtypes analyses showed that rs2811712 was associated with B-hyperdiploid ALL. These results provide evidence for the influence of genetic variants at CDKN2A/B locus with the risk of developing B-ALL.

CDKN2A and CDKN2B Gene Variants in Acute Lymphoblastic Leukemia in Tunisian Population

“…Gutierrez-Camino reported a positive association between rs3731249 and ALL risk in Spanish population. Also this variant is associated with B-ALL subtypes, including B-hyperdiploid ALL, and ETV6-RUNX1 ALL [25].…”

“…This SNP is a mis-sense variant, associated with C-to-T substitution resulting in alanine-to-threonine replacement [25]. This substitution induces a missense change for p16INK4A open reading frame, reduce the capacity of tumor suppressor CDK4 and CDK6 that favorite the B cell proliferation [23].…”

“…In addition, the association of CDKN2B rs662463 in ANRIL, regulates CDKN2B expression by disrupting a transcription factor binding site for CEBPB with ALL will also be investigated [24,25].…”

Polymorphism analysis of miR182 and CDKN2B genes in Greek patients with primary open angle glaucoma

“…[28] Regarding the rs3731249, the genotyping analyses were also performed by using PCR followed by restriction analysis, as previously described. [38] Statistical analysis.…”

The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia

“…Some genetic variants are found to be clinically relevant and can be associated with higher or lower risks of cardio and neurodegenerative diseases [ 18 ]. Certain SNPs significantly increase chances of developing cancer [ 20 ], including pediatric leukemia [ 21 , 22 ], while acquisition of somatic mutations in non-coding and untranslated regions of RNA transcripts as well as dysregulated expression of ncRNAs acting in trans play an important role in neoplasm development and progression [ 23 , 24 ].…”