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

• Published in: Genome medicine Vol. 15; no. 1; p. 25
• Main Authors: Nacer, Deborah F, Vallon-Christersson, Johan, Nordborg, Nicklas, Ehrencrona, Hans, Kvist, Anders, Borg, Åke, Staaf, Johan
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 14.04.2023; BioMed Central; BMC
• Subjects: Analysis; Biomarkers; BRCA1 protein; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - genetics; Cancer; Cancer and Oncology; Cancer och onkologi; Cancer patients; Cell growth; Clinical Medicine; Clinical screening; Development and progression; Diagnosis; ErbB-2 protein; Family medical history; Female; Gene expression; Gene variants; Genealogy; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic screening; Genetic Testing; Germ Cells; Germ-Line Mutation; Health aspects; Hereditary breast cancer; Humans; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Microenvironments; Molecular subtypes; Observational studies; Patients; Population studies; Population-based studies; Public health; RNA; RNA sequencing; Triple Negative Breast Neoplasms - diagnosis; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumor Microenvironment; Tumors; Womens health; Sweden; Molecular subtypes; Hereditary breast cancer; Gene expression; Clinical screening; Gene variants
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-023-01177-4

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. 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. 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. 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. The Sweden Cancerome Analysis Network - Breast (SCAN-B) was prospectively registered at ClinicalTrials.gov under the identifier NCT02306096.