Abstract
Introduction: Hematopoietic stem cell transplantation (HSCT) has been only option for treatment of acute myeloid leukemia (AML) refractory to induction chemotherapy. However, only less than 10% of patients can achieve long-term survival by HSCT in refractory AML. We hypothesized that certain donor genotype may confer leukemia clearing effects after HSCT in long-term survivors of refractory AML. This genotype may also associate with favorable clinical outcome of HSCT in AML with complete remission.
Methods: From 1985 to 2015, we retrospectively reviewed AML patients with HSCT from sibling donor at refractory status after induction and salvage chemotherapy in Seoul National University Hospital (SNUH). Only long-term survivors (> 30 months after HSCT) were included in training cohort. Whole-exome sequencing (WES) to discover specific donor germline genotype compared to corresponding patients' included in the training cohort. Considering cure rate of AML by HSCT, we focused on shared genotypes of donors in the training cohort, as high-effect, common variants. To validate the shared, specific donor genotype, called leukemia-clearing genotype (LCG), survival analysis of AML patients with HSCT in their complete remission status (SNUH validation cohort) were performed according to donor's LCG. Survival analysis according to germline LCG in The Cancer Genome Atlas (TCGA) was also validated for biologic significance of LCG.
Results: Twelve pairs of germline DNAs of donor and refractory patient were initially analyzed, among them, 5 sibling pairs were enrolled in the training cohort and finally analyzed. Gerrmline WES analysis of 5 donors resulted in 45,493 donor specific variants. Filtering out low allele carrier, variants in 1000 Genomes database, and poor quality reads, only 2 variants were remained and significant for known interaction, which were EGFR c.2982C>T and CDH11 c.945G>A, as LCGs. In SNUH validation cohort, among a total of 96 pairs of donor-patient, 22 (22.2%) donors had both LCGs in their germline DNA. Interestingly, overall survival of patients who received HSCT from donors with germline LCGs were significantly prolonged compared to others (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.24-0.94, log rank P= 0.033). In TCGA cohort, patients who had germline LCGs had favorable prognosis in both pan-cancer analysis (HR 0.83, 95% CI 0.69-0.99, log rank P= 0.048) and especially stomach adenocarcinoma (HR 0.44, 95% CI 0.21-0.95, log rank P= 0.037).
Conclusions: Germline variants of EGFR c.2982C>T and CDH11 c.945G>A, or LCGs, have phenotypically cancer-clearing effects when transplants to AML patients, and TCGA analysis showed patients with both LCGs are related to favorable prognosis. Prospective evaluation if donor with germline LCGs are related to favorable clinical outcome of HSCT should be warranted.
No relevant conflicts of interest to declare.
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