Molecular characteristics of breast tumors in patients screened for germline predisposition from a population-based observational study

Abstract

Background Pathogenic germline variants (PGVs) in certain genes are linked to higher lifetime risk of developing breast cancer and can influence preventive surgery decisions and therapy choices. Public health programs offer genetic screening based on criteria designed to assess personal risk and identify individuals more likely to carry PGVs, dividing patients into screened and non-screened groups. How tumor biology and clinicopathological characteristics differ between these groups is understudied and could guide refinement of screening criteria. Methods Six thousand six hundred sixty breast cancer patients diagnosed in South Sweden during 2010–2018 were included with available clinicopathological and RNA sequencing data, 900 (13.5%) of which had genes screened for PGVs through routine clinical screening programs. We compared characteristics of screened patients and tumors to non-screened patients, as well as between screened patients with (n = 124) and without (n = 776) PGVs. Results Broadly, breast tumors in screened patients showed features of a more aggressive disease. However, few differences related to tumor biology or patient outcome remained significant after stratification by clinical subgroups or PAM50 subtypes. Triple-negative breast cancer (TNBC), the subgroup most enriched for PGVs, showed the most differences between screening subpopulations (e.g., higher tumor proliferation in screened cases). Significant differences in PGV prevalence were found between clinical subgroups/molecular subtypes, e.g., TNBC cases were enriched for BRCA1 PGVs. In general, clinicopathological differences between screened and non-screened patients mimicked those between patients with and without PGVs, e.g., younger age at diagnosis for positive cases. However, differences in tumor biology/microenvironment such as immune cell composition were additionally seen within PGV carriers/non-carriers in ER + /HER2 − cases, but not between screening subpopulations in this subgroup. Conclusions Characterization of molecular tumor features in patients clinically screened and not screened for PGVs represents a relevant read-out of guideline criteria. The general lack of molecular differences between screened/non-screened patients after stratification by relevant breast cancer subsets questions the ability to improve the identification of screening candidates based on currently used patient and tumor characteristics, pointing us towards universal screening. Nevertheless, while that is not attained, molecular differences identified between PGV carriers/non-carriers suggest the possibility of further refining patient selection within certain patient subsets using RNA-seq through, e.g., gene signatures. Trial registration The Sweden Cancerome Analysis Network – Breast (SCAN-B) was prospectively registered at ClinicalTrials.gov under the identifier NCT02306096.

Kataegis in clinical and molecular subgroups of primary breast cancer

“…Clinicopathological and molecular characteristics of the 235 SCAN-B patients’ tumors are summarized in Table 1 . Based on FPKM data, gene expression-based rank scores for eight biological metagenes in breast cancer originally defined by Fredlund et al 14 were calculated as described by Nacer et al 26 . Pathology estimated proportions of tumor-infiltrating lymphocytes (TILs) on whole slide H&E sections were obtained from ref.…”

“…Of the 265 cases, 183 were ER-positive (ERp) (ERpHER2p or ERpHER2n). Based on FPKM data, gene expression-based rank scores for eight biological metagenes in breast cancer originally defined by Fredlund et al 14 were calculated as described by Nacer et al 26 . Rank scores were computed individually for each tumor without any normalization or data centering (i.e., they represent single sample scores).…”

Molecular mechanism of oroxyli semen against triple-negative breast cancer verified by bioinformatics and in vitro experiments

“…Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. [ 1 ] Its high metastatic potential and chemoresistance make it a challenging type of breast cancer to treat. [ 2 ] Currently, research on TNBC mainly focuses on the molecular biology mechanisms of the disease and targeted therapies.…”