Abstract GS2-06: Exploring the causal role of the human gut microbiome in breast cancer risk using mendelian randomization

Abstract

Background: Variation in the human gut microbiome may influence cancer progression and therapy response through various mechanisms including modulation of both immune and cell signalling pathways. Whilst observational epidemiological studies have provided evidence that the gut microbiome may play a role in cancer risk, such studies are prone to residual confounding, reverse causation, and other forms of bias. Therefore, the nature of these associations still remains unclear. Mendelian randomization (MR) is a causal methodology that uses genetic variants as instruments (“proxies”) for risk factors to eliminate such biases when questioning causality in observational epidemiological associations. The statistical power and precision of MR analyses can be increased by employing a “two-sample MR” (2SMR) framework in which summary data – usually from large, independent, genome-wide association studies (GWASs) reporting associations of genetic variants with exposures (here, the gut microbiome) and outcomes (here, cancer) – are synthesised to estimate causal effects of each exposure on each outcome of interest. In this study, we utilised 2SMR to interrogate causal relationships between the gut microbiome and breast cancer (BC) risk using the largest published GWASs of the gut microbiome and of clinically utilised subtypes of BC. Methods: We performed 2SMR using summary-level data from the GWAS of the host genetic contribution to gut microbiome variation amongst European individuals (the Flemish Gut Flora Project and two German cohorts (n=3890)) combined with summary-level data from the GWAS of BC risk (Breast Cancer Association Consortium (133,384 cases stratified by Luminal A, Luminal B, Human Epidermal Growth Factor 2 (Her2) positive, Her2 negative and triple negative status and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with BC)). Sensitivity analyses were also conducted to assess pleiotropy of genetic variants on BC risk, independent of gut microbiota. Analyses were conducted in R Studio using the TwoSampleMR and the MR-TRYX packages. Results: Of the 14 microbial traits (MTs) with evidence for a host genetic contribution in the GWAS of the gut microbiome, we found evidence that abundance of a genus within a certain bacterial order decreased the risk of triple negative BC (odds ratio per standard deviation increase: 0.84; 95% CI: 0.71, 0.9; p=0.03). In addition, we demonstrated that the risk of all molecular subtypes of BC may be altered by variation in these MTs, and that these relationships differed according to subtype. Sensitivity analyses demonstrated that pleiotropy was unlikely to explain these relationships Conclusions: In our study, we utilised two recent and novel GWASs in an MR context to appraise causality in relationships between the gut microbiome and BC risk and found evidence that certain bacteria may alter BC risk, effects of which vary according to molecular subtype. These important results generate hypotheses about mechanisms underlying the causal biology of BC subtypes and potentially facilitate the design of BC risk-reducing interventions and prevention strategies. Citation Format: Tim Robinson, Grace Edmunds, Bryony Hayes, Kaitlin Wade. Exploring the causal role of the human gut microbiome in breast cancer risk using mendelian randomization [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-06.

Update Breast Cancer 2021 Part 1 – Prevention and Early Stages

“…In the past, the gut microbiome has already been linked to the efficacy of immunotherapy in cancer patients [49]. The association between gut microbiome and breast cancer risk has also been studied [50] by now based on an existing large case-control study of over 130 000 breast cancer cases and more than 110 000 controls [51]. Moreover, studies were included that had investigated the correlation between genetic variants and the presence of specific microbiome patterns [52].…”

“…In the overall population, the bacterial genus ruminococcus was identified as a risk factor. In triple-negative breast cancer (TNBC), bacteria of the genus parabacteroides have been identified as protective and unclassified bacteria of the order bacteroidales as risk factors [50]. However, as the interaction between health and the microbiome is not yet fully understood, it is difficult to establish a risk-reducing interventional strategy based on this data.…”

Update Mammakarzinom 2021 Teil 1 – Prävention und frühe Krankheitsstadien

“…[49]. Nun wurde auch der Zusammenhang zwischen Darmmikrobiom und Brustkrebsrisiko untersucht [50] wobei auf eine bestehende große Fallkontrollstudie mit mehr als 130 000 Brustkrebsfällen und mehr als 110 000 Kontrollen zurückgegriffen wurde [51]. Weiterhin wurden Studien berücksichtigt, welche die Assoziation von genetischen Varianten und dem Auftreten von spezifischen Mikrobiommustern untersucht hatten [52].…”

“…In der Gesamtpopulation wurden Bakterien der Art Genus Ruminococcus als Risikofaktor identifiziert. Für das triple-negative Mammakarzinom (TNBC) wurden Bakterien der Gattung G. Parabacteroides als protektiv und unklassifizierte Bacteroidales-Bakterien als Risikofaktoren identifiziert [50]. Da die Zusammenhänge zwischen Gesundheit und dem Mikrobiom noch nicht vollständig geklärt sind, ist es jedoch schwierig, eine risikoreduzierende Intervention anhand dieser Daten zu etablieren.…”

Breast Cancer Prevention: Where Are We?

“…18 Some studies have suggested that folic acid might have a protective effect in those who consume alcohol on a regular basis 19,20 although this has not been confirmed in prospective, randomized clinical trials. There are several other areas of interest in breast cancer prevention including looking at the gut microbiome, 21 ruxolitinib in patients with premalignant breast lesions, 22 aspirin use in preventing recurrence, 23 and topical tamoxifen. 24 Some of the most interesting data from the WHI have been the studies looking at hormone replacement therapy (HRT).…”