Clinical Utility of Whole-Genome Analysis as One-for-All Test for Breast Cancer: A Case Series

Abstract

Introduction: Breast cancer exhibits vast genomic diversity, leading to varied clinical manifestations. Integrating molecular subtyping with in-depth genomic profiling is pivotal for informed treatment choices and prognostic insights. Whole-genome clinical analysis provides a holistic view of genome-wide variations, capturing structural changes and affirming tumor suppressor gene loss of heterozygosity.

Case presentation: Here we detail four unique breast cancer cases from Seoul St. Mary's Hospital, highlighting the actionable benefits and clinical value of whole-genome sequencing (WGS). As an all-in-one test, WGS demonstrates significant clinical utility in these cases, including: (1) detecting homologous recombination deficiency with underlying somatic causal variants (case 1), (2) distinguishing double primary cancer from metastasis (case 2), (3) uncovering microsatellite instability (case 3), and (4) identifying rare germline pathogenic variants in TP53 gene (case 4). Our observations underscore the enhanced clinical relevance of WGS-based testing beyond pinpointing a few driver mutations in conventional targeted panel sequencing platforms.

Conclusion: With genomic advancements and decreasing sequencing costs, WGS stands out as a transformative tool in oncology, paving the way for personalized treatment plans rooted in individual genetic blueprints.

Keywords: Breast cancer; Comprehensive genomic profiling; Whole-genome sequencing.

Fig. 1.

a Circos plot of breast cancer genome of case 1. From the outside of the circle to the inside, the following elements are arranged in their respective orders: cytoband, variant allele fraction of point mutations, intermutational distance of point mutations (logarithmic scale), copy number of each allele (red lines represent major, blue lines represent minor), total copy number (represented by black dots), and structural variations (represented by colored lines). b Somatic BRCA2-disrupting structural variation (inversion) between BRCA2 gene and DGKH gene and loss of heterozygosity in BRCA2 gene (minor copy number: 0).

Fig. 2.

Circos plot of cancer genome and HRD score of case 2. a Right breast. b Left ovary.

Fig. 3.

a Circos plot of breast cancer genome of case 3. b Sequencing and computational assessment of microsatellite instability (MSI) status by MSIsensor2. c Pentaplex PCR assessment of MSI status. d Immunohistochemical assessment of MSI status.

Fig. 4.

Complex arrangement of germline TP53 in case 4.