Whole genome sequence analysis suggests intratumoral heterogeneity in dissemination of XXXX to lymph nodes.

@entity1 @entity36570 @entity0 @entity5 @entity52789 @entity14410 @entity876 @entity3 @entity72011 @entity14583
BACKGROUND: Intratumoral heterogeneity may help drive resistance to targeted therapies in @entity5 . In @entity0 , the presence of nodal metastases is a key indicator of poorer overall survival. The aim of this study was to identify somatic genetic alterations in early dissemination of @entity0 by whole genome next generation sequencing (NGS) of a primary @entity0 , a matched locally-involved axillary lymph node and healthy normal DNA from blood. METHODS: Whole genome NGS was performed on 12   g (range 11.1-13.3   g) of DNA isolated from fresh-frozen primary @entity0 , axillary lymph node and peripheral blood following the DNA nanoball sequencing protocol. Single nucleotide variants, insertions, deletions, and substitutions were identified through a bioinformatic pipeline and compared to CIN25, a key set of genes associated with @entity5 @entity3 . RESULTS: Whole genome sequencing revealed overlapping variants between the @entity5 and node, but also variants that were unique to each. Novel mutations unique to the node included those found in two CIN25 targets, @entity36570 and @entity52789 , which are related to transcription cyclin activity and chromosomal stability, respectively, and a unique frameshift in @entity14410 , which is required for accurate sister chromatid segregation during cell division. We also identified dominant clonal variants that progressed from @entity5 to node, including SNVs in @entity876 and @entity72011 , which mediates rearrangements to the cytoskeleton and cell shape, and an insertion in @entity14583 , the expression of which is significantly associated with @entity5 proliferation and can segregate @entity0 by outcome. CONCLUSION: This case study provides preliminary evidence that @entity5 and early nodal @entity3 have largely overlapping somatic genetic alterations. There were very few mutations unique to the involved node. However, significant conclusions regarding early dissemination needs analysis of a larger number of @entity1 samples.
