|dc.description.abstract||Background: Breast and endometrial cancers are the most common gynaecological
cancers in women in the UK. Early detection of tumours is crucial for improving
patient survival rates. In breast cancer, mammography is the most reliable screening
method for asymptomatic patients; however, its sensitivity is limited by breast
density. Currently, there are no early screening assays for endometrial cancer. Thus,
there is an urgent need to identify clinical biomarkers for improved non-invasive
diagnosis of breast and endometrial cancer. Macrophages are abundant in the tumour
microenvironment and their density has been associated with poor prognosis in
breast cancer and decreased survival in endometrial cancer. Monocytes are
precursors of macrophages and recent studies have shown an association with pro-tumoral
functions. The aim of this study has been to examine the transcriptional
profiles of human circulating monocytes and tumour associated macrophages
(TAMs) in order to investigate their biological relevance and potential as biomarkers
for cancer detection and prognosis.
Methods: RNA-sequencing was performed on purified monocytes (22 healthy
individuals, 21 breast cancer, 16 endometrial cancer samples), as well as purified
normal macrophages, TAMs from breast tissue (4 breast cancer, 4 healthy breast)
and endometrium tissue (5 endometrial cancer, 9 healthy endometrium).
Results: A shift in the transcriptional profile of monocytes in cancer compared to
controls was observed. Given these cancer-associated alterations circulating
monocytes from cancer patients were called “Tumour Educated Monocytes”
(TEMo). A TEMo-derived 13-gene signature was extracted that detected cancer,
yielding an accuracy of 94%, a positive predictive value (PPV) of 92% and a
negative predictive value (NPV) of 97%. External validation confirmed the ability of
the signature to accurately identify cancer patients with perfect accuracy.
Transcriptome profiling of TAMs revealed a significantly altered gene expression
profile when compared to normal tissue resident macrophages. Furthermore,
comparison of TAMs between breast and endometrial cancer also revealed
differences suggesting that different tumour microenvironments induce different
gene expression profiles in TAMs. Functional analysis of significant genes in breast
cancer revealed similar biological pathways to those of murine studies suggesting
that TAMs in humans and mice may have similar functions. A gene list of
transmembrane receptors has been extracted by comparing breast cancer TAMs with
publicly available datasets that could serve as markers for their identification.
Finally, exploratory analysis identified a subset of 49 genes associated with
recurrence-free and overall survival in publicly available datasets.
Conclusion: To my knowledge this is the first genome-wide profiling study of
human circulating monocytes and TAMs in breast and endometrial cancer. It
provides evidence that monocytes and TAMs can alter their expression profile in the
presence of cancer and, using bioinformatics tools I was able to identify biomarkers
for diagnosis and prognosis of breast and endometrial cancer.||en