Cancer risks among first-degree relatives of women with a genetic predisposition to breast cancer

Qingyang Xiao; Xinhe Mao; Alexander Ploner; Felix Grassmann; Juan Rodriguez; Mikael Eriksson; Per Hall; Kamila Czene

doi:10.1093/jnci/djae030

Cancer risks among first-degree relatives of women with a genetic predisposition to breast cancer

J Natl Cancer Inst. 2024 Feb 14:djae030. doi: 10.1093/jnci/djae030. Online ahead of print.

Authors

Qingyang Xiao¹, Xinhe Mao¹, Alexander Ploner¹, Felix Grassmann², Juan Rodriguez¹, Mikael Eriksson¹, Per Hall^{1

3}, Kamila Czene¹

Affiliations

¹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
² Institute for Clinical Research and Systems Medicine, Health and Medical University, Potsdam, Germany.
³ Department of Oncology, Södersjukhuset, Stockholm, Sweden.

PMID: 38366028
DOI: 10.1093/jnci/djae030

Abstract

Background: Associations between germline alterations in women and cancer risks among their relatives are largely unknown.

Methods: We used women from two Swedish cohorts (KARMA and pKARMA), including 28,362 women with genotyping data and 13,226 with sequencing data. Using Swedish Multi-Generation Register, we linked these women to 133,389 first-degree relatives. Associations between protein-truncating variants (PTVs) in 8 risk genes and breast cancer polygenic risk score (PRS) in index women and cancer risks among their relatives were modeled via Cox regression.

Results: Female relatives of index women who were PTV carriers in any of the 8 risk genes had an increased breast cancer risk compared to those of non-carriers (HR1.85, 95% CI: 1.52-2.27), with the strongest association found for PTVs in BRCA1/2. These relatives had a statistically higher risk of early-onset than late-onset breast cancer (P = .001). Elevated breast cancer risk was also observed in female relatives of index women with higher PRS (HR per SD: 1.28, 95% CI: 1.23-1.32). The estimated lifetime risk was 22.3% for female relatives of PTV carriers and 14.4% for those related to women in the top PRS quartile. Moreover, relatives of index women with PTV presence (HR: 1.30, 95% CI: 1.06-1.59) or higher PRS (HR per SD: 1.04, 95% CI: 1.01-1.07) were also at higher risk of non-breast-HBOC cancers, including prostate, ovarian, pancreatic cancer, and melanoma.

Conclusions: Both PTVs of risk genes and higher PRS in index women are associated with an increased risk of breast and other HBOC-related cancers among relatives.