Author: George Weiner
Date: 2017-08-14 16:08:57

Incredible advances in cancer genetics have revolutionized how we think about cancer. These advances are now being applied to patient care. A brief response to the question "how is our growing knowledge of cancer genetics impacting on cancer research and cancer medicine?" is to say "it's complicated - and exciting!" That is not a very helpful answer. Here, I will summarize the big picture with the understanding that this brief summary will not even touch on some of the rapidly evolving, nuanced, yet very exciting concepts in cancer genetics.

Let's start out with a review and discussion of why the genetics revolution in cancer is so important.

The classic central dogma of biology that still holds true today (with many caveats), is that the coded genetic information we inherited from our parents is hard-wired into the DNA in every cell in our body. This DNA is transcribed into RNA which contains the program for synthesis of individual proteins. These proteins determine how our cells (and therefore our bodies) behave and respond to our environment. The bottom line is that DNA acts as the blueprint that determines how cells and our bodies behave. A gene is a region of DNA that is the molecular unit of heredity that is transcribed into RNA and, again with many caveats, results in a specific protein. The “genome” is all of the DNA in our bodies.

The year 2000 was a landmark year in human genetics when the announcement was made that essentially all 3 billion base pairs (letters in the DNA alphabet) of the human genome had been determined (or stated in more scientific language – sequenced).  The technology used to sequence and analyze DNA has advanced at an incredible pace since then. The original effort to sequence the human genome cost billions of dollars - now for just a few thousand dollars, we can more accurately sequence a genome in a week or so.

The initial determination of the human genome sequence was based on DNA from normal cells. This sequence is known as "germline DNA". The same germline DNA is present in every cell in an individual's body. DNA variants in some genes that impact on cancer risk, such as the gene known as BRCA1, were identified even before the human genome was fully sequenced. However, sequencing the human genome accelerated our ability to understand how variants in germline DNA can impact on the risk of getting cancer.

How do we use this information to help our patients? We know variants in germline DNA can impact on the chance of getting specific cancers. We can test for these variants. Such genetic tests are best interpreted when viewed along with the history of cancer in the patient and his/her family. Holden now has four full time genetic counselors who assist in this increasingly complicated but important service. Our genetic counselors collect family histories from patients who appear to have a higher than normal risk of cancer, recommend what genetic testing can be done, help interpret the results of genetic tests and make recommendations to the patients, their families and their health care providers. In some cases, this recommendation may focus on a program of more robust screening for cancer. In rare cases, the combination of gene testing and family history indicates such a high risk of developing cancer that surgery (e.g. prophylactic mastectomy) is considered to reduce the risk of developing cancer.

We are continuing to develop new and better approaches to evaluating the germline DNA in patients, and getting better at interpreting the results of such testing. Despite remarkable and ongoing progress, there is still room for improvement, and there is much we don't know about the genetics of cancer risk. My own family is an example. We have a strong family history of cancer that includes my grandfather, mother, father, aunts, uncles, sister.  Yet, my sister had genetic testing because of ovarian cancer diagnosed in when she was in her early 50s. This genetic testing was "negative", i.e. no known high risk DNA variants were identified. This doesn't mean our family members don't have any gene variants that increase our risk of developing cancer, just that they haven't been identified yet.

Thus far, I have been discussing germline DNA we inherit from our parents that are present in every cell in the body. What about cancer cells themselves? If mutations in our germline DNA occur in just the wrong piece of DNA in a single cell, it can result in that cell behaving badly and becoming cancerous. These mutations can occur spontaneously, or be induced by carcinogens such as tobacco smoke. Only a tiny fraction of mutations can cause cancer, but one mutation or a combination of mutations in DNA in a single cell at the wrong place and the wrong time can cause trouble by over-activating or under-activating particular genes. Some cancer-causing mutations result in over-activation of genes that control growth of the cell. These are known as oncogenes. Other mutations in cancer cells can cause under-activation of genes that normally prevent a cell from duplicating abnormally. These are known as tumor suppressor genes.

Many years ago, we had hoped to find a small subset of DNA mutations that were responsible for most cancers. If only that had been so! Research has identified hundreds of oncogenes and tumor suppressor genes, and thousands of individual mutations that can result in genes behaving badly and can lead to cancer. In other words, there is huge variability in the mutational profile of cancers. Cancers from two different patients that develop in the same organ and look the same under the microscope are with rare exceptions caused by unique mutations.

Does this complexity mean studying mutations in DNA in cancer is useless? NO! While the specific mutations found in cancers are more often than not unique to each individual, the number of pathways by which mutations cause cancer cells to behave badly are more limited. Two different mutations in the same pathway can have similar effects on the behavior of the cancer. Using information we have gained from studying cancer mutations, we have identified key cancer pathways, and are developing anti-cancer drugs that target these pathways. Thus, while the number of individual mutations that are capable of causing cancer is almost limitless, careful interpretation of mutations in individual patients is providing valuable information that is being used to select the best treatment for an individual patient. Importantly, there is a growing list of targeted cancer medicines, developed from our understanding of mutations that cause changes in cancer pathways.

At Holden, we have worked with our colleagues in the Department of Pathology to develop world-class molecular pathology capabilities so we can analyze and interpret cancer DNA mutations for individual patients. We hold a molecular tumor board to review cancer DNA mutation results from our patients and discuss next steps. We are also part of a collaboration of 15 other cancer centers known as the Oncology Research Information Exchange Network (or ORIEN for short) that I blogged about earlier this year. ORIEN is designed to accelerate research progress by sharing information on cancer genetics. Within a few years, we expect to see continued improvements in our ability to detect mutations, analyze their importance, and identify targeted treatment for patients based on those mutations.

There are many other related topics that are fascinating but too complex to discuss here. Among them - passenger versus driver mutations, epigenetics, heterogeneity of tumor genetics, RNA sequencing, non-coding RNA, the microbiome, circulating tumor DNA, liquid biopsies, gene therapy, rational drug design, etc, etc, etc. So... no doubt cancer genetics is complicated - and exciting, and we are just beginning to scratch the surface on using this information to help our patients. Stay tuned!