This article provides some basic genomic concepts and facts. It is hoped that this post will be helpful to understanding and asking questions. As human beings, we have 46 chromosomes (23 pairs) with a total of roughly 20,000 protein-coding genes. In addition to these protein-coding genes, there are large portions of non-coding DNA within the genome which we do not really understand the function of. All together, these 46 chromosomes make up our genome and are found in every cell of our body.
We inherit two copies of every gene, one from our mother and one from our father, except for the 23rd chromosome which contains the sex-linked genes. Of the roughly 20,000 protein-coding genes, we understand the function of a relatively small fraction, and of these, a few hundred have been implicated directly in cancer. The exact number of cancer involved genes varies from a low of about 80 to a high of about 500 depending upon the researcher’s opinion and definition of “cancer-involved”. Abnormalities in these cancer-implicated genes include: amplifications (too many copies of the gene), deletions (too few or no copies of the gene), truncations (sections deleted), mutations (a part copied incorrectly), and fusions (two genes fused together). When a protein-coding gene is amplified, it is likely (although not certain) that too much of the protein produced by the gene is created causing the gene to be over-active. When a gene is deleted, truncated or mutated, not enough (or any) of the protein is produced causing the gene to be inactivated.
Gene fusions are believed to create onco-proteins which can be thought of as mutated proteins which behave weirdly and drive the bad behavior of the cancer cell. However, exactly how this occurs isn’t really understood. One really important thing to keep in mind about genomics is that while our understanding is growing by leaps and bounds, the reality is that our understanding is still in the toddlerhood of genomics. The human genome was first fully sequenced in 2004 and it was the first animal to be sequenced. That’s only 15 years ago which is little more than the blink of an eye in terms of scientific research.
Cancer Cell Genomics
Now, a brief discussion on cancer cell genomics. Every second of every day in our bodies, our cells are growing and dividing. An adult human is estimated to have somewhere between 20-40 trillion cells. A rough estimate of how long it takes a cell to grow and divide is about a day, but that varies widely from as few 10 minutes to upwards of a year. When a cell divides, we usually get two daughter cells identical to the original mother cell. However, every so often, there are mistakes in the cell division. Most of the time these mistakes are cleaned up as part of the DNA damage repair response in our cells. However, sometimes they are not and when they are not, a cancer cell can result.
Cancer cells are often killed off by our immune system before they get a chance to grow and divide. Our bodies do this all the time, every day, without stopping. However, sometimes a cancer cell will figure out how to avoid the immune system and when that happens, they can grow and divide unchecked, and a cancerous tumor results. While the cancer may have started because of a series of genetic abnormalities, the very genetic instability which caused the cancer cell in the first place often leads to additional instability within the cancer cell. This instability allows the cancer cell to keep mutating in response to therapy or simply because. We don’t know enough about how this happens. What has been observed however, is that tumors are not homogeneous throughout themselves, and that metastases are often different from one another and from the primary tumor. This all leads to significant questions about to treat tumors based on genetics.
Theresa Beech’s (volunteer researcher) research and that of Dr Alejandro Sweet-Cordero at University of California, San Francisco seem to indicate that for osteosarcoma tumors, there are certain patterns in the genomics which repeat again and again. There also seem to generally be driving genes within osteosarcoma which repeat again and again from primary tumor to metastasis and then subsequent metastasis. There does, however, seem to be one significant subset of osteosarcomas that does not follow this general principle. The primary tumor and the mets are all extremely different genetically. These tumors appear to be driven by certain very strong germline mutations. The hypothesis is that what may actually be occurring is that there may be multiple spontaneous osteosarcoma tumors occurring at once due to the strong germline mutation. This is a hypothesis right now and not definitive, and based on Ms. Beech’s research, this is a relatively small subset of osteosarcomas.