AI research discovers link between smell genes and colon cancer

Research from Dr Heba Sailem, recently published in Molecular Systems Biology, showed that patients with specific smell-sensing genes ‘turned on’ are more likely to have worse colon cancer outcomes.

Through the development of a machine-learning approach to analyse the perturbation of over 18,000 genes, Dr Sailem and her team found that olfactory receptor gene expression may have some effect on the way that colon cancer cells are structured.

Dr Sailem used layers of Artificial Intelligence (AI), including computer algorithms, to detect the changes of cancer cell appearance and organisation when the genes are turned down using siRNA technology. AI played a crucial part of this research, as it allowed for speed and efficient analysis and mapping of cell image data to various gene functions that were studied, which greatly increase the amount of information that can be extracted and reduced human error.

Dr Sailem surveyed over 18,000 genes and found that specific smell-sensing genes called olfactory receptor genes are strongly associated with how colon cancer cells spread and align with each other akin to the changes induced by turning down key colon cancer genes.

The practical patient implications of this research include how we might approach patients with colon cancer, depending on their genetic makeup. In the long run, Dr Sailem hopes that these findings will allow clinicians to survey patient genes, create specific predictions based on their genetics and create tailored treatments to best treat their cancer.

There is already a large body of research into the genes that influence the structure of cancer tissues, but studies such as this might help to find new target genes. For example, by reducing the expression of olfactory genes, we could potentially inhibit cancer cells from spreading and eventually invading other tissues which is the major cause of cancer death

About the Author

Dr Heba Sailem is a Sir Henry Wellcome Research Fellow at the Big Data Institute and Institute of Biomedical Engineering at the University of Oxford. Her research is focused on developing intelligent systems that help further biological discoveries in the field of cancer.

This paper is a result of three years of work, focusing on identifying the role of genetic expression on the spread and management of colon cancer.

Future research

Following this research Dr Sailem hopes to apply this AI approach to a wider range of cancer, to see what genes are associated with and influence cancer tissue structure, proliferation and motility.

For more information about this research, see Dr Heba Sailem’s paper here.

Oxford researchers discover DNA repair protein complex important in drug resistance in cancers driven by BRCA mutations.

A team of Cancer Centre researchers lead by Associate Professor Ross Chapman have discovered a novel DNA repair protein complex called ‘Shieldin’.

Published in Nature, the paper describes the identification of ‘Shieldin’, which was shown to be essential for generating genetic diversity in antibodies produced during immune responses.

When activated following an infection or immunisation, B cells activate the expression of enzymes that induce multiple breaks in the genes encoding the different antibody fragments. Highly specialised DNA repair proteins are essential for the generation of the deletions and mutations required to generate new antibody genes, which enables the production of antibodies with different or improved specificities towards an antigen. Researchers found Shieldin binds to specific DNA structures present at the ends of DNA breaks formed during these processes, and was essential for their repair.

Shieldin was found to link the adaptive immune system to a mutagenic DNA repair process associated with the progression of hereditary breast and ovarian cancers caused by BRCA1 mutations.

Commenting on the link between DNA, the immune system and cancer, Associate Professor Ross Chapman, lead author of the study and group leader at the Wellcome Centre for Human Genetics remarked “For some time, my lab has been puzzled over why a DNA repair pathway that normally only functions in the immune system, is also the primary pathway responsible for cancers driven by BRCA1 gene mutations. In finding Shieldin, we have taken a major step in answering this question. DNA breaks generated during antibody class-switch recombination are known to have single stranded DNA tails at their ends. The fact that Shieldin binds these structures and promotes their repair, also suggests that the recognition and repair of similar DNA structures by Shieldin when the BRCA1 protein is no longer functional, may be what leads to the mutations that cause cancer.”

The group’s findings also provide new insights into how cancer cells can become resistant to anti-cancer drugs: “PARP inhibitors are proving to be an extremely powerful drugs to treat cancers driven by BRCA mutations, however a lot of these cancers are known to then go on to develop resistance. Our work shows mutations that effect any of the four Shieldin proteins will render these cancers completely resistant to PARP inhibitors. By working out exactly how Shieldin works, we hope to identify secondary vulnerabilities in these resistant cancers, which can be exploited in anti-cancer therapies to counteract the threat of this resistance.”

Sarah Blagden Associate Professor of Experimental Cancer Medicine & Consultant Medical Oncologist, and Director of Early Phase Cancer Trials Unit & Oxford ECMC lead, emphasises the importance of the new findings: “In this paper, Ross Chapman and his team have unpicked the main method of DNA damage repair in patients with BRCA1 mutations called non-homologous end joining (NHEJ). By comparing NHEJ in different cellular processes they have shown that, in cells lacking BRCA1, NHEJ is reliant on the four-protein complex Shieldin. Not only do they indicate Shieldin is responsible for the cancers that develop in patients with BRCA1 mutations, but also that Shieldin drives resistance to PARP inhibitors. Chapman’s findings are important in our understanding of why it is that patients with BRCA1 mutations that are taking PARP inhibitors like olaparib, rucaparib or niraparib eventually become resistant to them. By providing these new insights into BRCA1 biology, they open future avenues for tackling PARP resistance and improving outcomes for BRCA1-cancer patients in the future.”

This project was funded by Medical Research Council (MRC) Grant (MR/ M009971/1) and Cancer Research UK Career Development Fellowship (C52690/A19270) awarded to J.R.C.