Program: Oral and Poster Abstracts
Type: Oral
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis: New Genomic Discoveries in Acute Lymphoblastic Leukemia
We first identified a family with three cases of childhood ALL at St. Jude Children’s Research Hospital. Whole exome sequencing of this family (mother and 2 daughters with ALL, the unaffected father and 1 unaffected daughter) identified a single variant in ETV6 (p.R359X) in the 3 cases with ALL and also in the healthy daughter. This nonsense variant is predicted to create a stop codon within the ETS domain of ETV6, resulting in a truncated protein without DNA-binding function. This highly damaging variant is likely to be responsible for the ALL predisposition in this family with a high albeit incomplete penetrance. To comprehensively determine the prevalence of ALL-predisposing alleles in ETV6, we performed targeted sequencing of this gene in 4,405 children with newly-diagnosed ALL enrolled on the Children’s Oncology Group (COG) AALL0232, P9904, P9905 and P9906 protocols and St. Jude Total Therapy XIIIA, XIIIB and XV studies. We identified a total of 43 germline variants in the exonic regions of ETV6. Thirty-one of the 43 ETV6 variants were defined as “ALL-related” because they were not found or extremely rare in non-ALL populations (N=60,706). These ALL risk variants included 4 nonsense, 21 missense, 1 splice site, and 5 frameshift variants occurring in 35 children (0.79% of ALL cases studied). Fifteen of the 31 ALL-related variants (48.4%) were clustered in the ETS DNA-binding domain of ETV6. We used the combined annotation dependent depletion algorithm (CADD) to predict deleterious effects of each variant. ALL-related ETV6 variants were significantly more likely to be damaging compared to germline variants observed in the non-ALL population (mean CADD phred-like score of 25.6 vs 15.2, respectively, p<0.0001). Interestingly, of the 18 most deleterious ETV6variants, 10 (55.6%) resided in the ETS domain although none were located within the helix directly interacting with target DNA. Instead, 7 of the 10 variants in ETS domain were between the first and second helices.
We next analyzed the relationship between germline risk variants in ETV6 and clinical features of ALL in a subset of 2,021 cases enrolled on St. Jude and COG frontline ALL trials. These cases were comprehensively evaluted for ALL charateristics and representative of the US childhood ALL population. Children with ALL-related ETV6 variants were significantly older at the time of diagnosis than those without these variants (9.5 years vs 6.4 years; P=0.009). The hyperdiploid leukemia karyotype was strikingly overrepresented in ALL cases harboring germline ETV6 risk variants compared to the wildtype group (64.3% vs 26.8%; P=0.0045). In contrast, the frequency of somatic ETV6-RUNX1 fusion was much lower in cases with ETV6 germline risk variants, compared to cases with wildtype ETV6 (7.1% vs 22.7%), even though this difference did not reach statistical significance. Of note, there was also a trend towards overrepresentation of females in carriers of ALL-related ETV6variants (71.4% vs 45.7%; P=0.063).
In conclusion, our findings indicate that germline ETV6 variations are important determinants for genetic predisposition to childhood ALL.
Disclosures: Martin: Jazz Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees ; Gentium SpA/Jazz Pharmaceuticals: Research Funding . Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping . Hunger: Spectrum Pharmaceuticals: Consultancy ; Jazz Pharmaceuticals: Consultancy ; Merck: Equity Ownership ; Sigma Tau: Consultancy .
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