Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification

Abstract

Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5–41% of breast cancers. Here, we investigated the genetic differences between HER2‐positive and HER2‐negative admixed breast cancer components. We performed an in‐depth analysis to explore the potential heterogeneity in the somatic mutational landscape of each individual tumour component. Formalin‐fixed, paraffin‐embedded breast cancer tissue of ten patients with at least one HER2‐negative and at least one HER2‐positive component was microdissected. Targeted next‐generation sequencing was performed using a customized 53‐gene panel. Somatic mutations and copy number variations were analysed. Overall, the tumours showed a heterogeneous distribution of 12 deletions, 9 insertions, 32 missense variants and 7 nonsense variants in 26 different genes, which are (likely) pathogenic. Three splice site alterations were identified. One patient had an EGFR copy number gain restricted to a HER2‐negative in situ component, resulting in EGFR protein overexpression. Two patients had FGFR1 copy number gains in at least one tumour component. Two patients had an 8q24 gain in at least one tumour component, resulting in a copy number increase in MYC and PVT1. One patient had a CCND1 copy number gain restricted to a HER2‐negative tumour component. No common alternative drivers were identified in the HER2‐negative tumour components. This series of 10 breast cancers with heterogeneous HER2 gene amplification illustrates that HER2 positivity is not an unconditional prerequisite for the maintenance of tumour growth. Many other molecular aberrations are likely to act as alternative or collaborative drivers. This study demonstrates that breast carcinogenesis is a dynamically evolving process characterized by a versatile somatic mutational profile, of which some genetic aberrations will be crucial for cancer progression, and others will be mere ‘passenger’ molecular anomalies.

Modeling Basins of Attraction for Breast Cancer Using Hopfield Networks

“…In this research, we observed that more than 20 gene inhibitions are required to move a tumor sample from the tumor toward the control basin of attraction. This result indicates that recovering a tumor sample back to the control state is not feasible, which may be explained by accumulation of genetic mutations, alteration in genes copy-number, and other processes that may not be regulated by drug administration (Van Bockstal et al, 2020). Rather, we identified the key genes responsible for attractor stability.…”

The clonal relation of primary upper urinary tract urothelial carcinoma and paired urothelial carcinoma of the bladder

“…This panel comprised 330 amplicons covering 41 genes, multiple hotspot regions in various cancer‐related genes and 154 single nucleotide polymorphisms in multiple tumor suppressor regions to detect copy number variations (Table 2 and Supplementary Table 3). 5‐7 NGS was performed with the Ion Torrent platform using supplier's materials and protocols (Thermo Fisher Scientific). Median coverage depths were 1994x for UTUC, 1712x for UCB and 1914x for the adjacent normal tissue.…”

Nuclear Insulinoma-Associated Protein 1 Expression as a Marker of Neuroendocrine Differentiation in Neoplasms of the Breast

“…3,5,6,18,[20][21][22] This low sensitivity might have been due to the use of tissue microarrays, wherein two 0.6 mm cores per tumor were included. 9 Breast carcinomas frequently present with intratumor heterogeneity, 23 and heterogeneous protein expression throughout the tumor might influence the evaluation of immunohistochemistry performed on tissue microarrays. Nevertheless, tissue microarrays allow for immunohistochemical analysis of new biomarkers in extremely large cohorts, which enables clinicopathological correlations.…”