Background: The CDKN2A/B locus is inactivated in several haeamatologic malignancies mainly due to deletion, aberrant repression or epigenetic silencing, but little is known about the potential role of its single nucleotide polymorphisms (SNPs) in leukemia susceptibility. Patients and methods: To investigate whether polymorphisms within this locus can correlate with increased susceptibility to haeamatologic malignancies, an association study was performed by genotyping 23 SNPs spanning the MTAP, CDKN2A/B and CDKN2BAS loci, as well as relative intergenic regions, in a case-control cohort made up of 332 samples: 149 leukemia patients, including Philadelphia positive (Ph+) ALL (n=92) and acute myeloid leukemia (AML) samples (n=57), and 183 unrelated healthy controls. The median age was 52 years (18-78 years) and 53 years (21-71 years) in Ph+ ALL and AML patients, respectively. AML cases included FAB M0-M5, miscellaneous cytogenetic abnormalities and normal karyotype subtypes. 6 SNPs were selected on the basis of their previous association with several diseases, such as coronary artery disease, type 2 diabetes mellitus, frailty. The remaining 17 SNPs were selected among those included in the Affymetrix Genome-Wide Human SNP Array 6.0 to deepen the SNPs coverage for the examined region. Genotyping was performed using iPLEX Gold technology and MassARRAY high-throughput DNA analysis with Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (Sequenom, Inc., San Diego, CA). Results: 17 SNPs, spanning the 9p genomic interval that encompasses the MTAP, CDKN2A/B and CDKN2BAS loci, were successfully genotyped and used for investigating their potential associations with the leukemia phenotypes. Potential population stratification affecting the control sample was ruled out as its genotypes distribution satisfies the Hardy-Weinberg equilibrium criterion. The rs564398, mapping to the CDKN2BAS locus that encodes for ANRIL antisense non-coding RNA, showed a statistically significant correlation with the ALL phenotype, with a risk pattern that was compatible with an overdominant model of disease susceptibility and an Odd Ratio (OR) of 2 (95% CI, 1.20 to 3.33; p = 7.1 × 10-3). Since a co-ordinated regulation of ANRIL and p14/ARF, p16/CDKN2A, p15/CDKN2B transcription has been already observed in both physiologic and pathologic conditions, we hypothesized that rs564398 association reflects a condition of high linkage disequilibrium between such polymorphism and a causative variant that is able to alter CDKN2A/B expression profiles by changing ANRIL dosage, thus leading to abnormal proliferative boosts and consequent increased ALL susceptibility. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, Ateneo RFO grants, Project of integrated program, Programma di Ricerca Regione – Università 2007 – 2009.

A germline polymorphism in the ANRIL (CDKN2BAS) locus is associated with susceptibility to Philadelphia-positive acute lymphoblastic leukemia (ALL)

Anna Ferrari;Ilaria Iacobucci;Marco Sazzini;Annalisa Lonetti;Alessio Boattini;Cristina Papayannidis;Mariachiara Abbenante;Vilma Mantovani;Viviana Guadagnuolo;Federica Cattina;Elena Marasco;Emanuela Ottaviani;Stefania Paolini;Simona Soverini;Michele Baccarani;Giovanni Martinelli
2011

Abstract

Background: The CDKN2A/B locus is inactivated in several haeamatologic malignancies mainly due to deletion, aberrant repression or epigenetic silencing, but little is known about the potential role of its single nucleotide polymorphisms (SNPs) in leukemia susceptibility. Patients and methods: To investigate whether polymorphisms within this locus can correlate with increased susceptibility to haeamatologic malignancies, an association study was performed by genotyping 23 SNPs spanning the MTAP, CDKN2A/B and CDKN2BAS loci, as well as relative intergenic regions, in a case-control cohort made up of 332 samples: 149 leukemia patients, including Philadelphia positive (Ph+) ALL (n=92) and acute myeloid leukemia (AML) samples (n=57), and 183 unrelated healthy controls. The median age was 52 years (18-78 years) and 53 years (21-71 years) in Ph+ ALL and AML patients, respectively. AML cases included FAB M0-M5, miscellaneous cytogenetic abnormalities and normal karyotype subtypes. 6 SNPs were selected on the basis of their previous association with several diseases, such as coronary artery disease, type 2 diabetes mellitus, frailty. The remaining 17 SNPs were selected among those included in the Affymetrix Genome-Wide Human SNP Array 6.0 to deepen the SNPs coverage for the examined region. Genotyping was performed using iPLEX Gold technology and MassARRAY high-throughput DNA analysis with Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (Sequenom, Inc., San Diego, CA). Results: 17 SNPs, spanning the 9p genomic interval that encompasses the MTAP, CDKN2A/B and CDKN2BAS loci, were successfully genotyped and used for investigating their potential associations with the leukemia phenotypes. Potential population stratification affecting the control sample was ruled out as its genotypes distribution satisfies the Hardy-Weinberg equilibrium criterion. The rs564398, mapping to the CDKN2BAS locus that encodes for ANRIL antisense non-coding RNA, showed a statistically significant correlation with the ALL phenotype, with a risk pattern that was compatible with an overdominant model of disease susceptibility and an Odd Ratio (OR) of 2 (95% CI, 1.20 to 3.33; p = 7.1 × 10-3). Since a co-ordinated regulation of ANRIL and p14/ARF, p16/CDKN2A, p15/CDKN2B transcription has been already observed in both physiologic and pathologic conditions, we hypothesized that rs564398 association reflects a condition of high linkage disequilibrium between such polymorphism and a causative variant that is able to alter CDKN2A/B expression profiles by changing ANRIL dosage, thus leading to abnormal proliferative boosts and consequent increased ALL susceptibility. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, Ateneo RFO grants, Project of integrated program, Programma di Ricerca Regione – Università 2007 – 2009.
2011
Anna Ferrari, Ilaria Iacobucci, Marco Sazzini, Annalisa Lonetti, Alessio Boattini, Cristina Papayannidis, Mariachiara Abbenante, Vilma Mantovani, Viviana Guadagnuolo, Federica Cattina, Elena Marasco, Emanuela Ottaviani, Stefania Paolini, Domenico Girelli, Simona Soverini, Michele Baccarani, Giovanni Martinelli
File in questo prodotto:
Eventuali allegati, non sono esposti

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/628385
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 0
social impact