Somatic variations in Human Cancer Genomes

Somatic deletions have complex mechanisms formed by replication errors which drive
somatic rearrangements but can result from multiple mechanisms; even in a single genome
both DNA strands break
Genetic alterations: single nucleotide variations, structural variations, aneuploidy
Somatic single nucleotide variations for specific tumor types have mutational signatures
typical to their mismatch repair deficiency and mutagenic exposure ( UV, smoking,
chemotherapy)
Large structural variations include deletions, insertions, more complex alterations; driving
mechanism ?
Mechansims for SV known:
o Homologous recombination (DNA repair mechanism)highly accurate except for in
nonallelic homologous recombination pairing between incorrect homologous
regions
o Nonreplicative nonhomologous repair-nonhomologous endjoining; requires no
homology and generates microhomology and small insertions at the deletion
breakpoints
o Complex rearrangements: fork stalling and template switching mechanism: stall
replication at the fork and polymerase shift template via microhomology to any ear
by single stranded DNA resulting in inversion, tandem duplication, translocation
more complex etc.
Most common SV deletion+insertion or inversion at breakpoint via fork stalling template
switching or microhomology mediated break induced repair
Meerkat algorithm for predicting SV