The breast tumours of Asian, Black and White women have very different cellular, microbial and genomic features that could potentially be used to personalise care or predict disease progression, according to new research by investigators at the Johns Hopkins Kimmel Cancer Center.
Potential race-specific microbial biomarkers of breast cancer identified by the researchers correlated with genes involved in tumour aggressiveness, blood vessel growth, tumour cell migration and metastasis, and the cancer pathways GLI1 and Notch. The findings were published in the journal npj Breast Cancer.
“The factors governing racial disparities in breast cancer are multifactorial and can include socioeconomic status, access to primary care, timely referrals, and health and nutrition,” says senior study author Dipali Sharma, PhD, professor of oncology at the Johns Hopkins University School of Medicine and a John Fetting Fund for Breast Cancer Prevention researcher. “However, it is important to identify additional modifiers for these differences. Our study demonstrates that the microbiome and immune microenvironments of breast tumours also vary significantly among women of different ethnicities and could potentially be used as biomarkers to predict disease progression or response to treatment.”
Sharma and colleagues examined genomic and metagenomic data from The Cancer Genome Atlas cohort, which included 1,018 patients with breast cancer categorised into Asian (65 patients), Black (257 patients) and White (696 patients) groups via self-reporting. They used a web-based tool called xCell to analyze the specific 64-cell signatures of breast tumours among the patients, finding that 11 of the cell types showed very distinct, statistically significant variations among races. Cellular differences were most pronounced between tumours from Black and White women, while the tumours from Asian and Black women showed the least definitive differences compared to each other.
Researchers also observed a higher proportion of smooth muscle cells among tumours from Asian women in comparison to those from Black women. Adipocytes (cells that make up fat tissue) showed the least accumulation in the tumours from Asian women but a significantly higher proportion in tumours from White women. The proportion of haematopoietic stem cells – cells that give rise to all blood and immune cells – was significantly lower in tumours from Asian women compared with those from White women, while MEPs and Th1 cells were significantly higher in tumours from Asian women. Interferon-gamma, a substance important for immunity against infections, was higher in tumours from Asian women, while CXCL9, a substance that plays a role in immune activation, was overexpressed in tumours from Black women. Together, the tumour microenvironment-related changes observed in the tumours of Black women may support aggressive tumour progression.
In studies analyzing the bacterial community composition among these tumours, investigators found that breast tumour microbes in Asian women did not vary significantly from either Black or White women. However, the microbe compositions in breast tumours from Black and White women were significantly diverse from each other. Microbial biomarkers Acinetobacter, Citrobacter, Enterobacter, Staphylococcus, Paracoccus and Akkermansia were differentially abundant in breast tumours from Black women compared with those from White women, while Actinomyces and Veillonella were plentiful in breast tumours from White women in comparison to Black women. Pseudomonas and Methylobacter were among the microbial biomarkers recognised in Asian women.
Multiple pathways and processes were expressed differently in the tumours from the three racial groups as well. For example, several cancerous pathways were significantly upregulated in the tumours of Black women, including mTOR signalling, calcium signalling, Notch and WNT. ABC transporters, which are known to be responsible for the development of chemotherapy resistance in breast cancers, also were upregulated in tumours from Black women.
Looking at gene expression profiles, investigators found 394 differentially expressed genes between tumours from Asian women versus Black women. Some 381 differed between Black women versus White women, and 127 differed between Asian women versus White women.
Finally, investigators looked for correlations between genes and microbial biomarkers, finding that the gene GLI1 was positively correlated with a type of bacteria called Terrabacter in tumours from Asian and Black women. These results indicate a possible role of microbes in the blood vessel development of tumours and therefore warrant further investigation, says first author Sheetal Parida, PhD, research associate in the Department of Oncology at the Johns Hopkins University School of Medicine.
The group is planning to validate their findings in a larger cohort. They also want to determine how microbes in breast tumours affect disease progression, which could be via secreted metabolites, Sharma says, and to develop microbe-based biomarkers: “The study paves the path for further explorations as we try to understand this whole network more mechanistically.”
White women have the highest lifetime risk of breast cancer incidence (13%), compared with American Indian and Alaska Native (8%), Asian and Pacific Islander (11%), Black (12%) and Hispanic (11%) women. However, the risk of breast cancer in Black women under age 45 is 40% higher compared with their age-matched White counterparts, the paper noted.
Other study co-authors were Sumit Siddharth and Yuqing Xia of Johns Hopkins.