Authors
Josh N Vo, Yi-Mi Wu, Rui Wang, Tiffany Pham, Xuhong Cao, Sophie Yeung, Mingyu Park, Yelena Kleyman-Smith, Guo Ci Teo, Alyssa Wu, Anne Li, Jamie Estill, Lakshmi P Kunju, Chen Yang, Dan R Robinson, Arul M Chinnaiyan
Published in
medRxiv : the preprint server for health sciences. May 05, 2026. Epub May 05, 2026.
Abstract
Conventional short-read sequencing cannot determine whether co-occurring variants within a cancer gene reside on the same allele (cis) or on opposing alleles (trans), a distinction with direct biological and therapeutic consequences. Trans configurations confirm biallelic tumor suppressor inactivation and inform therapy selection, while cis configurations generate compound oncogenic alleles with enhanced activity. We analyzed 768 patients with prostate, breast, or ovarian cancers in the PROBLEM cohort, using mutational signatures to nominate cryptic genomic instability cases where the causative biallelic event was not apparent from short-read sequencing. Long-read nanopore sequencing resolved 32 of 46 cryptic cases (69.6%), leveraging its unique advantages in direct methylation detection, long insertion resolution, and complex structural variant characterization, confirming trans biallelic inactivation in all resolved tumor suppressor cases. Systematic analysis of 4,496 MiOncoSeq samples identified 17,519 multi-hit gene pairs, of which 78.7% exceeded the 500 bp short-read phasing limit. Long-read phasing further revealed recurrent compound cis oncogenic alleles in NOTCH1, PIK3CA, PDGFRB, and KIT with functionally synergistic activity. Haplotype phasing resolves a systematically overlooked gap in cancer variant interpretation and warrants broader integration into precision oncology workflows.
PMID:
42145645
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.
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