Analysis of Even a Limited Number of Genes Indicates a Strong Inherited Component in Otherwise Typical Sporadic MDS

Somatic mutations are frequently found in patients with MDS. Germline (GL) alterations are less common, in part due to sequencing panels limited to mutations seen commonly in myeloid malignancies, with further exploration only pursued in patients with a clear indication of a familiar disease. It is common to have GL cases where family history is not as informative as we expect, given unreliable recollection by patients and premature mortality of family members. The recognition of pathogenic GL variants is difficult due to the tremendous numbers of inconsequential SNPs, unclear pathologic significance of most new/rare variants and the lack of paired tumor/GL DNA. GL variants may be affecting risk as i) predisposing factors to seemingly sporadic adult MDS or ii) known "leukemia genes" with variable penetrance or longer latency due to lesser functional impact than canonical defects seen in childhood. In addition, there is an ongoing debate as to the role of heterozygous variants of recessive traits serving as predisposition factors. Either way, GL variants may constitute a non-clonal first hit with a long latency until clinical manifestation.To determine the percentage of MDS cases whose etiology may be related to GL mutations, we screened for GL alterations in two sets of selected genes, i) genes often affected by somatic mutations in MDS (n=65), ii) genes known to predispose to bone marrow failure, leukemia or other cancers (n=105). We focused on Tier 1 variants only.We analyz...
Source: Blood - Category: Hematology Authors: Tags: 636. Myelodysplastic Syndromes-Basic and Translational Studies: Poster II Source Type: research