Inherited Germline DNA Repair Gene Defects Are Prevalent Among Thai Patients with Myeloid Neoplasms

Certain germline mutations increase the risk of developing myeloid neoplasms (MNs) accompanied by second hit somatic events, such as therapy-related or oxidation-induced DNA damages. Aberrancy in DNA damage response (DDR) pathways leads to genomic instability giving rise to cancer. Previous data showed that the prevalence of pathogenic germline mutations in young adult Caucasian MN patients was 13-19%.^{1, 2} The most commonly affected pathways were involved in telomere biology and transcription factors, while the defects in DDRs were found in 15-25%. However, data in Asians are limited.

In this study, we investigated the prevalence and landscape of germline variants in cancer predisposition genes in a cohort of Thai patients diagnosed with MNs. Targeted next generation sequencing of 23 germline predisposition genes was performed using the SureSelect custom kit and the Illumina HiSeq 2500 system. The total of 127 unselected adult (> 15 years old) patients from 3 medical centers comprising MDS (66%), MDS/MPN (14%) secondary AML (sAML, 20%) were enrolled. The median age was 66 years old (range 16-93) and 50% were male. Variants reported in COSMIC, the frequency of higher than 0.01% in the Genome Aggregation Database (gnomAD) or Thai exome database (consisted of 1084 Thai exome controls) and variant allelic frequency of less than 30% were excluded. New or exceeding rare nonsense variants or indels, as well as missense variants predicted to be deleterious by at least 4/6 in silico software, were included. The variants were classified according to American College of Medical Genetics (ACMG) classification. 14pathogenic and likely pathogenic germline variants were identified in 15 patients (15/127; 12%). One patient had 2 variants including heterozygous CEBPA^P75fs and MSH2^A604G. Of the 16 variants, there were 8 (50%) missense, 7 (44%) frameshift, and 1 (6%) nonsense, with a median VAF of 51%, ranging 36-83%. The variants affected the DDR pathway (8/16; 50%), transcriptional regulation pathway (4/16; 25%) and signal transduction pathway (2/16; 13%). Two variants were recurrent i.e.,FANCA^{Ala1219GlyfsTer59} and BRCA2^{Glu626delinsAspPro} and the others were identified in BRCA1/2, MSH2, MSH6, GATA2, CEBPA, DDX41, CBL and NF1. The median age of patients harboring germline variants was younger (58 vs. 66 years old) than those who did not. Half of the cases (6/12) were characterized by normal cytogenetics without enrichment of -7 or complex karyotype, comparable to patients with no germline variants. Of note, 28% (4/14) patients had previous history of gastrointestinal stromal tumor, Graves’ disease, Immune thrombocytopenia, and aplastic anemia (FANCA mutation) for years before MNs were diagnosed. None of the patients reported family history of hematological malignancies.

In conclusion, the prevalence of germline predisposition to MNs in Southeast Asian populations is as high as in Caucasians and the identified variants are more commonly involved in the DDR pathway. The defects in the DDR pathway suggested an important role of genomic instability in leukemogenesis. This subset of patients should preferably receive non-cytotoxic treatments to avoid oxidative damages that possibly lead to further clonal evolution.

References

1. Keel SB, Scott A, Sanchez-Bonilla M, Ho PA, Gulsuner S, Pritchard CC, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica 2016 Nov; 101(11): 1343-1350.

1. Feurstein S, Churpek JE, Walsh T, Keel S, Hakkarainen M, Schroeder T, et al. Germline variants drive myelodysplastic syndrome in young adults. Leukemia 2021 2021/08/01; 35(8): 2439-2444.

No relevant conflicts of interest to declare.