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Analysis of Complicated Subclonal SCNAs in Cancer Samples: Evaluating Solutions

This study presents a detailed analysis of challenging cancer samples characterized by extensive subclonal structural copy number alterations (SCNAs) and single nucleotide variants (SSNVs). Multiple solutions were evaluated, with preferences shifting between them due to issues like low purity, high complexity, and an unlikelihood of genome doubling. A simpler solution was ultimately favored due to its clearer multiplicity peak and lower complexity, despite some discrepancies in initial calls. Future updates of analysis tools like ABSOLUTE are anticipated to refine these findings.

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Analysis of Complicated Subclonal SCNAs in Cancer Samples: Evaluating Solutions

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  1. Challenging sample due to subclonal SCNAs – Prefer 1st solution

  2. Extensive subclonal SCNAs – but 1st solution looks correct.

  3. Possible genome doubling? Unlikely, because of SSNV data – no or few SSNVs at multiplicity=1 in doubled solution (below) – this would imply that no SSNVs occurred between doubling and sampling (unlikely) Prefer 1st solution

  4. Prefer 2nd solution – genome doubling does not help explain the SCNAs. Also – 1st solution SSNV multiplicity peak at 1.4 – bad fit.

  5. A challenging sample due to a small # of subclonal populations having extensive SNCAs – tendency to over-fit with high-ploidy solution. Notice that solution #1 has allelic balance of 0.17 at CN=3 – this is very unlikely to be real (only expect balance at powers of 2). Prefer much simpler solution #6 (below)

  6. OOPS – ABSOLUTE did not find the correct mode – this happens rarely – will be fixed in future releases – for now leave these uncalled.

  7. Challenging sample – likely a ‘bad’ SNP hybridization Prefer 2nd solution – lower complexity. Also – excellent multiplicity peaks.

  8. A challenging sample – extensive apparent subclonal SCNAs / SSNVs Prefer 2nd solution (low ploidy) – due to lower complexity

  9. A challenging sample: low purity + subclones Prefer 2nd solution due to LOH peak

  10. Calling with no SCNAs: SSNVs only You need to override the ‘non-aneuploid’ status in the calls file (change to ‘1’ in this case). This will be fixed in future version (when SSNVs are present).

  11. A strange call by ABSOLUTE (oops) – no apparent reason to prefer 1st solution – override to 2nd simpler solution. Hopefully fixed in future version.

  12. Some unusual Karyotypes – Near haploid genomes (a,b). Uncommon, but found in lung adeno, GBM, stomach cancer, and assorted other cancers. Hyperploid (>6n) (c)

  13. Genome doubling or not? Tough call – even with SSNVs.

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