Intratumor heterogeneity can lead to cancer progression, and tumors with the highest levels of heterogeneity may be more likely to progress. Researchers compared mutational loads from separate areas of pure ductal carcinoma in situ (DCIS) to genetic heterogeneity in DCIS lesions that coexist with invasive cancer and presented the findings at the San Antonio Breast Cancer Symposium on December 6, 2018.

Researchers identified cases of pure DCIS (n = 41) and DCIS diagnosed concurrent with invasive cancer (n = 30). They macro-dissected two areas of DCIS from each case a minimum of 0.8 cm apart, as well as control tissues and DNA extracted from formalin-fixed paraffin-embedded (FFPE) samples. The investigators developed new bioinformatics methods that allowed for analysis of small amounts of degraded DNA extracted from FFPE samples across multiple regions.

The investigators performed whole-exome sequencing on two geospatially separated blocks for each case. To be included in the analysis, samples must have had 40 mutations over at least 50% of the exome. Researchers measured intratumor heterogeneity based on the ratio of private mutations (in one area) to public mutations (found in both areas).

The overall mutational load of DCIS was not a significant predictor of progression; however, patients with DCIS adjacent to invasive disease had a higher ratio of private versus public mutations in coding domains (p = 0.016).

Functional analysis of mutated coding genes demonstrated a statistically significant enrichment in signal transduction, olfactory receptors, and cell-matrix interactions in both tumor types, after correcting for false discovery rate (FDR). DCIS adjacent to invasive disease had an enrichment of mutated genes involved in additional cellular functions such as microtubule activity (FDR = 0.002), protein-protein interactions (FDR = 5.11), and extracellular matrix remodeling (FDR = 0.02).

“Our findings suggest that functional heterogeneity may play an important evolutionary role as a driver for invasive progression,” the researchers noted.