#WorldCancerDay
February 2 is celebrated as World Cancer Day. A special Facebook post by NAS members Yuan Chang and Patrick Moore on the NAS Facebook page to commemorate the day. Below is the full text of the post along with resources for further reading.
Today’s post is written by NAS members Yuan Chang and Patrick Moore, who are married. Both research cancer at the University of Pittsburgh Cancer Institute. Recently, Chang and Moore received the Paul Ehrlich and Ludwig Darmstaedter Prize and the Passano Foundation Prize for discovering two of seven known human viruses that directly cause cancer:
In the early 1990s, before the advent of effective antiretroviral drugs, Kaposi sarcoma (KS) was a harbinger for the AIDS epidemic. Dozens, then hundreds, and ultimately hundreds of thousands of previously-healthy, young, gay and bisexual men starting getting KS, a rare cancer. This seemed almost unbelievable since no cancer had behaved like this before. Finding out what caused KS became a major scientific dilemma.
By 1993 we were at Columbia University (Chang) and the NYC Department of Health (Moore). We thought we might be able to answer this question by directly isolating a viral nucleic acid from a tumor rather than trying to culture the virus. We had no grants and only $15,000 in research funding. But researchers at Cold Spring Harbor had developed a method to physically subtract two different genomes from each other--leaving only sequences that are different. We thought that if this were applied to a KS tumor and healthy tissue from the same patient, the two samples would be genetically identical except the difference could be DNA from a new virus causing the cancer. It worked.
We found two small DNA fragments belonging to a new herpesvirus, Kaposi sarcoma herpesvirus (KSHV or HHV8)[1]. With Ethel Cesarman, we isolated larger fragments. Another form of cancer, primary effusion lymphoma, was found to be infected with this virus. From this point, we could grow the virus in cells[2], develop blood tests[3,4] and then sequence the KSHV genome[5].
Finding the virus, however, was just the beginning since rigorous analyses were needed to show that it actually causes KS. It took about two years to prove that KSHV was the cause of KS. Now it is clear that every KS tumor is infected with KSHV. KSHV causes cancers in people who are infected with it and also have suppressed immune systems, whether due to AIDS, transplantation, aging, or another factor.
The technique we used to find KSHV has limits and isn’t practical for finding most other tumor viruses. We knew, however, that for most viral tumors every tumor cell is infected. Each tumor cell has at least one nonhuman RNA molecule (belonging to the virus) that produces an oncoprotein driving cell division. The trick would be to find these nonhuman RNAs in tumors suspected to be caused by a virus.
Starting in 1999, we spent the next eight years doing preliminary experiments, going through trials-and-errors, and perfecting this approach into a method called digital transcriptome subtraction (DTS).[6] Instead of physically subtracting tumor sequences (as we had done with KSHV), we would sequence the RNA molecule (mRNA) from a tumor and use DTS to computationally “subtract” known human sequences, leaving only those that might belong to a new virus. Merkel cell carcinoma, like KS, occurs in immunosuppressed persons and so Huichen Feng from our lab in 2007 tried DTS on these tumors. Two weeks later, we found that DTS worked[7].
DTS uncovered Merkel cell polyomavirus (MCV). MCV was the first human pathogen discovered by non-directed sequencing, an approach that is now commonplace in any research laboratory looking for new viruses (others, such as Matt Meyerson at Harvard University independently also developed this approach). Unlike KSHV, most of us harmlessly carry this virus in our skin. But Masahiro Shuda found that cancer arises when the virus becomes mutated[8]. This is a new idea: specific mutations to our normal viral flora, rather than to a host cell, can lead to a human cancer. We have barely begun to understand the viruses that we always carry with us.
Research on KSHV and MCV has been exciting with some of the best labs in the world using these viruses to make breakthroughs in cancer research, immunology and microbiology. This has led doctors to use new immune checkpoint therapies resulting in near-miraculous cures for some MCC patients.
Sadly, public policy and pharmaceuticals have lagged far, far behind science for KSHV. KS is still the most common cancer in Africa, parts of South America, and Western China. Scientists know nearly everything needed to develop practical vaccines, diagnostics and targeted therapies for this cancer but there is little or no interest in developing treatment for a disease that mostly affects poor and marginalized populations. The next breakthrough awaits someone who harnesses this science to change the course of this cancer
- Chang, Y., et al., Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science, 1994. 265: p. 1865-69.
- Cesarman, E., et al., In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences. Blood, 1995. 86(7): p. 2708-14.
- Moore, P.S., et al., Primary characterization of a herpesvirus agent associated with Kaposi's sarcoma. J Virol, 1996. 70(1): p. 549-58.
- Gao, S.-J., et al., Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. New Eng J Med, 1996. 335: p. 233-241.
- Russo, J.J., et al., Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl Acad Sci U S A, 1996. 93(25): p. 14862-7.
- Feng, H., et al., Human transcriptome subtraction by using short sequence tags to search for tumor viruses in conjunctival carcinoma. J Virol, 2007. 81(20): p. 11332-40.
- Feng, H., et al., Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science, 2008. 319(5866): p. 1096-100.
- Shuda, M., et al., T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci U S A, 2008. 105(42): p. 16272-7.doi:10.1130/0016-7606(1970)81[1001:MOTCEO]2.0.CO;2.
|
Yuan Chang You can read more about Dr. Chang's work |
Patrick S. Moore You can read more about Dr. Moore's work via his NAS member profile. |
