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Molecular Differences between Screen-Detected and Interval Breast Cancers Are Largely Explained by PAM50 Subtypes
Jingmei Li1, Emma Ivansson2,3, Daniel Klevebring2
1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. jingmei.li@ki.se.
Summary
Interval breast cancers show molecular differences compared to screen-detected ones, but these are mostly explained by PAM50 subtypes. This study provides insights into aggressive tumor biology.
Area of Science:
- Genomics and Transcriptomics
- Cancer Biology
- Breast Cancer Research
Background:
- Interval breast cancers are clinically significant due to their aggressive nature and ability to evade screening mammography.
- Understanding the genomic and transcriptomic drivers of interval cancers is crucial for improving early detection and treatment strategies.
- The Clinical Sequencing of Cancer in Sweden (Clinseq) platform enables comprehensive genomic profiling of tumors.
Purpose of the Study:
- To comprehensively characterize the somatic genomic and transcriptomic differences between interval and screen-detected breast cancers.
- To identify specific genetic mutations, copy number aberrations, and gene expression patterns associated with interval cancers.
- To investigate the influence of mammographic density and PAM50 molecular subtypes on observed molecular differences.
Main Methods:
- Targeted deep sequencing of cancer-related genes, low-pass whole-genome sequencing, and RNA sequencing were applied to 173 breast tumors (113 screen-detected, 60 interval).
- Analysis focused on identifying somatic mutations, copy number alterations, and differentially expressed genes between interval and screen-detected groups.
- Mammographic density and PAM50 molecular subtypes were incorporated into the analysis to adjust for their potential impact.
Main Results:
- Univariate analysis revealed significantly higher mutation frequencies for TP53, PPP1R3A, and KMT2B in interval cancers.
- Distinct somatic copy number aberrations, including gains in 17q23-q25.3 and losses in 16q24.2, were observed more frequently in interval cancers.
- While 447 differentially expressed genes were identified, most molecular differences between interval and screen-detected cancers were no longer significant after adjusting for PAM50 subtypes.
Conclusions:
- Molecular distinctions exist between interval and screen-detected breast cancers, but these are predominantly attributed to underlying PAM50 molecular subtypes.
- The study provides valuable insights into the biological characteristics that may contribute to the aggressive phenotype of interval breast cancers.
- Further research is needed to fully elucidate the specific drivers and mechanisms underlying interval breast cancer development and progression.
