Associations between Pathogenic Germline Variants in BRCA and Non-Breast/Non-Ovarian Cancer Types in the German Population

Abstract

Introduction

Families with pathogenic germline variants (pv) in BRCA1/2 may have besides breast and ovarian cancer an elevated lifetime risk for other cancer types.

Material and Methods

Data and pedigree information from 1852 family members of 286 BRCA1/2 positive families were analyzed. Genetic testing was conducted between 2015 and 2017 at the HBOC center at Charité – Universitätsmedizin Berlin. Relative cancer risk (RR) was calculated by comparing observed cancer incidence with the expected incidence in the German population.

Results

BRCA1/2 positive families showed an elevated cancer risk for gastric and cervical cancer regardless of BRCA status. The relative risk of gastric cancer was higher in BRCA2 carriers compared to BRCA1 carriers (gBRCA1 RR 1.42; 95% CI: 0.65–2.69 vs. gBRCA2 RR 1.88; 95% CI: 0.75–3.87). Similarly, the relative risk for cervical cancer was also greater in BRCA2 carriers than in BRCA1 carriers (gBRCA1 RR 1.88; 95% CI: 0.69–4.09 vs. gBRCA2 RR 2.09; 95% CI: 0.56–5.35). Additionally, BRCA2 families showed an increased risk of pancreatic cancer (RR 1.56; 95% CI, 0.50 to 3.63). No significant associations were found for other cancer entities.

Conclusion

In the present study, an increased risk of gastrointestinal cancer was observed in German families with pathogenic BRCA1/2 variants, consistent with findings from previous research. Potential new associations with cervical cancer were also identified, warranting confirmation through large prospective studies. These findings highlight the importance of developing additional screening programs or preventive strategies for BRCA carriers, especially with regard to upper gastrointestinal tract malignancies.

Zusammenfassung

Einleitung

Pathogene Keimbahnvarianten (pV) in BRCA1/2 sind mit einem erhöhten Risiko für Mamma- und Ovarialkarzinome assoziiert. Mögliche Zusammenhänge mit einem gesteigerten Risiko für weitere Tumorentitäten werden ebenfalls vermutet.

Material und Methoden

Es wurden Daten von 1852 Familienmitgliedern aus 286 BRCA1/2-positiven Familien ausgewertet, die sich im Zeitraum von 2015 bis 2017 am HBOC-Zentrum der Charité – Universitätsmedizin Berlin vorgestellt hatten. Das relative Krebsrisiko (RR) wurde durch den Vergleich der beobachteten Krebsinzidenz in der Studienpopulation mit der erwarteten Inzidenz in der deutschen Allgemeinbevölkerung berechnet.

Ergebnisse

In BRCA1/2-positiven Familien zeigte sich ein erhöhtes Risiko für Magen- und Zervixkarzinome, unabhängig vom BRCA-Status. Das Risiko für ein Magenkarzinom war bei BRCA2-Träger*innen höher als bei BRCA1-Träger*innen (gBRCA1 RR = 1,42; 95%-KI 0,65–2,69 vs. gBRCA2 RR = 1,88; 95%-KI 0,75–3,87). Für Zervixkarzinome ergab sich ein ähnlicher Trend (gBRCA1 RR = 1,88; 95%-KI 0,69–4,09 vs. gBRCA2 RR = 2,09; 95%-KI 0,56–5,35). BRCA2-Familien zeigten zudem ein erhöhtes Risiko für Pankreaskarzinome (RR = 1,56; 95%-KI 0,50–3,63). Für andere Tumorentitäten ergaben sich keine signifikanten Assoziationen.

Schlussfolgerung

Pathogene BRCA-Varianten sind in der vorliegenden Studie mit einem erhöhten Risiko für gastrointestinale Tumoren in der deutschen Bevölkerung assoziiert. Diese Ergebnisse stimmen mit früheren Untersuchungen überein. Potenzielle Zusammenhänge mit einer erhöhten Inzidenz von Zervixkarzinomen sollten in größeren prospektiven Studien überprüft werden. Die Befunde unterstreichen die Bedeutung zusätzlicher Screening- und Präventionsstrategien für BRCA-Träger*innen, insbesondere im Hinblick auf Malignome des oberen Gastrointestinaltrakts.

Keywords

genetics - BRCA (breast cancer antigen) - cancer registry

Schlüsselwörter

BRCA1/2 - pathogene Keimbahnvarianten - gastrointestinale Malignome - Assoziation - Prävention

Publication History

Received: 06 July 2025

Accepted after revision: 29 October 2025

Article published online:
28 November 2025

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