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

Sep 21, 2026

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Background: Associations between germline alterations in women and cancer risks among their relatives are largely unknown. Methods: Women from two Swedish cohorts (KARMA and pKARMA) with genotyping or sequencing data were linked to first-degree relatives through the Swedish Multi-Generation Register. Cox regression modeled breast cancer risk using protein-truncating variants in eight risk genes and polygenic risk score. Results: Female relatives of variant carriers showed increased breast cancer risk (HR 1.85, 95% CI 1.52-2.27), with BRCA1/2 strongest, higher early-onset risk, and elevated risk also linked to higher polygenic risk score. Lifetime risk was 22.3% vs 14.4% across polygenic quartiles. Elevated risk extended to nonbreast hereditary breast and ovary syndrome-related cancers. Conclusions: Protein-truncating variants and higher polygenic risk score in index women increase breast and related cancer risks in relatives.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages10

Reading Time25 min

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Abstract

Background, Methods, Results, Conclusions

Introduction

Genetic predisposition and known risk variants

Links between breast cancer genes and other cancers

Prior studies and limitations

Study aim and cohort design

JNCI: Journal of the National Cancer Institute, 2024, 116(6), 911–919 [https://doi.org/10.1093/jnci/djae030](https://doi.org/10.1093/jnci/djae030) Advance Access Publication Date: February 14, 2024 Article Cancer risks among first-degree relatives of women with a genetic predisposition to breast cancer Qingyang Xiao , PhD,1,􀀃 Xinhe Mao , MD, MSc,1 Alexander Ploner , PhD,1 Felix Grassmann , PhD,2 Juan Rodriguez, PhD,1 Mikael Eriksson, PhD,1 Per Hall , MD, PhD,1,3 Kamila Czene , PhD1 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 2Institute for Clinical Research and Systems Medicine, Health and Medical University, Potsdam, Germany 3Department of Oncology, S€odersjukhuset, Stockholm, Sweden 􀀃 Correspondence to: Qingyang Xiao, PhD, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Nobels v€ag 12A, 171 77 Stockholm, Sweden ([e-mail: xiao.qingyang@ki.se](e-mail: xiao.qingyang@ki.se)) . Abstract Background: Associations between germline alterations in women and cancer risks among their relatives are largely unknown. Methods: We identified women from 2 Swedish cohorts Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) and prevalent KARMA (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 in 8 risk genes and breast cancer polygenic risk score in index women and cancer risks among their relatives were modeled via Cox regression. Results: Female relatives of index women who were protein-truncating variant carriers in any of the 8 risk genes had an increased breast cancer risk compared with those of noncarriers (hazard ratio [HR] ¼ 1.85, 95% confidence interval [CI] ¼ 1.52 to 2.27), with the strongest association found for protein-truncating variants in BRCA1 and 2. These relatives had a statistically higher risk of early onset than late-onset breast cancer (P ¼ .001) . Elevated breast cancer risk was also observed in female relatives of index women with higher polygenic risk score (HR per SD ¼ 1.28, 95% CI ¼ 1.23 to 1.32) . The estimated lifetime risk was 22.3% for female relatives of protein-truncating variant carriers and 14.4% for those related to women in the top polygenic risk score quartile. Moreover, relatives of index women with protein-truncating variant presence (HR ¼ 1.30, 95% CI ¼ 1.06 to 1.59) or higher polygenic risk score (HR per SD ¼ 1.04, 95% CI ¼ 1.01 to 1.07) were also at higher risk of nonbreast hereditary breast and ovary cancer syndrome-related cancers. Conclusions: Protein-truncating variants of risk genes and higher polygenic risk score in index women are associated with an increased risk of breast and other hereditary breast and ovary syndrome–related cancers among relatives. Female breast cancer became the most diagnosed malignancy worldwide and affected more than 2 million individuals in 2020 (1) . Genetic predisposition to breast cancer has been extensively studied. Association analyses using data of more than 113 000 women revealed that protein-truncating variants of CHEK2 , BRCA2 , ATM , BRCA1 , PALB2 , BARD1 , RAD51C , RAD51D , and TP53 were statistically significantly associated with breast cancer risk with large effect sizes (2) . In addition, genome-wide association studies have identified more than 200 common risk variants associated with marginally increased breast cancer risk, most of which are not within known risk genes (3) . However, the cumulative effect of the common risk variants, summarized as polygenic risk score, has a substantial impact on breast cancer risk (4 , 5) . Genetic predisposition to breast cancer has also been shown to be associated with other cancers. For instance, BRCA1 and 2 mutations are causative for hereditary breast and ovary cancers syndrome (6), with BRCA2 further imp

FAQs

What is the main research question of the study?

The study examines whether breast cancer risk and other hereditary cancer risks among first-degree relatives of women are associated with germline genetic factors in the index women, including protein-truncating variants and polygenic risk scores.

Which genetic factors were analyzed in the index women?

The analysis focused on protein-truncating variants in eight risk genes and the breast cancer polygenic risk score derived from the index women’s genetic data.

What were the key findings about relatives’ cancer risk?

Female relatives of index women who carried protein-truncating variants had increased breast cancer risk, higher early-onset risk, and elevated risk was also observed for relatives of women with higher polygenic risk scores; risks also extended to certain related nonbreast cancers.

Sep 21, 2026

Uploaded by Hazel