What Should We Be Worried About?

CURRENT SEQUENCING STRATEGIES IGNORE THE ROLE OF MICROORGANISMS IN CANCER

AZRA RAZA, M.D.

Professor of medicine; director, the MDS (Myelodysplastic Syndrome) Center, Columbia University

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

In the 1970s, it was 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 seventies were dedicated to combination chemotherapies. The eighties were dominated by a race to identify mutations in the human homologs 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 toward developing the Cancer Genome Atlas, utilizing high-throughput genome analysis to catalog 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, and new targets for treatment, will 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’s 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’s 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 that 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 resides 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 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 to 30 percent of 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, the community of microorganisms that live in our bodies. The microbiome makes up about 1 to 3 percent of our biomass and outnumbers human cells in the body by 10 to 1.

The Human Microbiome Project (HMP), a consortium of eighty universities and scientific institutions funded by the National Institutes 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.

Most 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 percent of DNA), has been mostly abbreviated to whole-exome sequencing (the gene-coding region, comprising about 2 percent 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 now the main focus of study for the investigators who continue to be the principal drivers of cancer research.

The second problem is that only the malignant cells are being studied by the vast majority of researchers, whereas 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 to study both the seed and the soil and to perform whole-genome sequencing rather than examining only 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 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.