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Updated: May 19, 2026

Comparative Lesions Analysis Through a Targeted Sequencing Approach

Comparative Lesions Analysis Through a Targeted Sequencing Approach

Published on: November 5, 2019

Long-Read Haplotype Phasing Resolves Allelic Configuration as a Missing Layer of Precision Oncology.

Josh N Vo^1,2,3, Yi-Mi Wu^1,2,3, Rui Wang^1,2,3

¹Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Medrxiv : the Preprint Server for Health Sciences

|May 18, 2026

Summary

Long-read sequencing accurately distinguishes cancer gene variants on the same (cis) or opposing (trans) alleles. This improves understanding of tumor suppressor inactivation and oncogene activation for precision oncology.

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Area of Science:

Genomics
Cancer Biology
Molecular Diagnostics

Background:

Short-read sequencing limits the resolution of co-occurring genetic variants within cancer genes, hindering the distinction between cis and trans configurations.
This distinction is critical as cis variants can create compound oncogenes, while trans variants indicate biallelic tumor suppressor inactivation, both impacting therapeutic strategies.

Purpose of the Study:

To evaluate the utility of long-read nanopore sequencing in resolving the cis/trans configuration of cancer gene variants.
To identify cryptic genomic instability cases missed by short-read sequencing.
To characterize the clinical and biological implications of variant phasing in cancer.

Main Methods:

Analysis of 768 prostate, breast, and ovarian cancer samples from the PROBLEM cohort using long-read nanopore sequencing.
Application of mutational signatures to identify cryptic genomic instability.
Systematic analysis of 4,496 MiOncoSeq samples to assess variant phasing limitations and identify recurrent cis/trans configurations.

Main Results:

Long-read sequencing resolved 69.6% of cryptic genomic instability cases, confirming biallelic tumor suppressor inactivation in all resolved cases.
78.7% of multi-hit gene pairs in 4,496 samples exceeded the short-read phasing limit.
Recurrent compound cis oncogenic alleles in NOTCH1, PIK3CA, PDGFRB, and KIT were identified, exhibiting functionally synergistic activity.

Conclusions:

Haplotype phasing using long-read sequencing effectively resolves a critical gap in cancer variant interpretation.
This approach enhances the understanding of tumor suppressor inactivation and oncogene activation.
Broader integration of long-read sequencing into precision oncology workflows is warranted for improved patient care.