2013 : WHAT *SHOULD* WE BE WORRIED ABOUT?

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Professor of Medicine, Director of the MDS Center, Columbia University
The Role Of Microorganisms In Cancer Is Being Ignored By The Current Sequencing Strategies

As a researcher studying cancer for almost four decades, I have witnessed several cycles during which the focus of its investigators has shifted radically to accommodate the prevailing technical or intellectual advances of the time.

In the 1970s it was newly discovered that while the use of single chemotherapeutic drugs produced impressive results in certain cancers, adding more agents could effectively double the response rate; thus the 70s were dedicated to combination chemotherapies. The 80's were dominated by a race to identify mutations in the human homologues of genes that cause cancers in animals (oncogenes).

This was followed in the 1990s by a focus on immune therapies and monoclonal antibodies resulting in some resounding successes in the treatment of lymphomas. Given the technical advances as a result of the Human Genome Project, the spotlight in this decade has now swung towards developing the Cancer Genome Atlas utilizing high throughput genome analysis to catalogue genetic mutations in some of the most common cancers.

The premise here is that by identifying mutations in cancer cells and comparing them to normal cells of the same individual, a better understanding of the malignant process will emerge and new targets for treatment would emerge. This is all very exciting, but if the current trend of sequencing the cancer genome continues unchanged, the role of pathogens in initiating and/or perpetuating cancer may be missed for a long time to come. Here is why.

Chances of getting cancer in a lifetime are 1 in 2 for men and 1 in 3 for women. The most widely accepted view is that cancer is a genetic disease. While there is no doubt that cancer is caused by mutated cells, the question is how do the mutations arise in these cells in the first place? Among several possibilities, there are at least two which could relate the presence of a cancerous growth to pathogens.

The first is that the individual is born with a mutated cell but the cell remains dormant because the microenvironment (soil) where it is residing may not be suitable for its proliferation. If the surrounding conditions change in such a way that the soil is now more fertile for the abnormal cell at the expense of normal cells, then the mutated cell could expand its clonal population resulting in a cancerous growth. It is a well appreciated fact that most cancers thrive in a pro-inflammatory microenvironment and pathogens are capable of altering a normal microenvironment to a pro-inflammatory one thus providing the required conditions for a mutated cell to grow.

A second possibility is that the pathogen actually infects a normal cell and co-opts its vital machinery resulting in unchecked growth of the mutated cells. Thus it is not unreasonable to look for the presence of a microorganism in either the malignant cell or in its microenvironment.

Studies have already demonstrated that 20-30% cancers worldwide are associated with chronic infection; the Epstein Barr virus can cause lymphomas and nasopharyngeal cancers, the human papillomavirus (HPV) causes cervical cancer and head and neck tumors, long term bacterial infection with Helicobacter pylori can cause stomach cancer and hepatitis B virus (HBV) causes liver cancer.

There is a good possibility that many more cancers will be associated with pathogens and some cancer causing pathogens may turn out to be part of our collective "microbiome" or the community of microorganisms that live in our bodies. The microbiome makes up about 1-3% of our biomass and outnumbers human cells in the body by 10 to 1.

The Human Microbiome Project (HMP), a consortium of 80 universities and scientific institutions funded by the National Institute of Health, is looking at this aspect tangentially through defining the communities of bacteria that live within the human body and their role in health and disease.

Unfortunately, HMP is only defining the communities of bacteria (and they have shown 10,000 species!) that live in our bodies but this will not help identify microorganisms associated with cancers. The reason that more cancers have not been associated with microorganisms thus far is because we lack suitable techniques for detecting devious pathogens like retroviruses. Unfortunately, only a small proportion of effort and money is being invested in this area of research.

The majority of researchers are studying malignant diseases through sequencing, but microorganisms associated with cancer will be missed because genomic sequencing which should involve whole genome sequencing (100% of DNA) has been mostly abbreviated to whole exome sequencing (gene coding region comprising ~2% of DNA).

This has happened at least in part because massive parallel sequencing is still not economically feasible or technically advanced enough for routine use. The problem is that the integration of a cancer causing pathogen is not likely to be in the coding region (exome) which is presently the main focus of study for the individual investigators who continue to be the principle drivers of cancer research.

The second problem is that only the malignant cells are being studied by the vast majority of researchers while the cancer causing microorganism may be residing in the cells of the tumor microenvironment, rendering the soil fertile only for the growth and expansion of the mutated cell. In order to develop a more comprehensive understanding of the cancerous process, it is important therefore to study both the seed and the soil and to perform whole genome sequencing rather than only examining the coding regions of the genome.

Carl Zimmer writes in his book Parasite Rex that "Parasites are expert at causing only the harm that's necessary, because evolution has taught them that pointless harm will ultimately harm themselves." Evolution will eventually teach the malignant cells and their masters that the only way they will truly succeed in perpetuating themselves is by immortalizing rather than killing the host. Let us hope we will have the answer to the cancer debacle before that.