where it shows up in medicine and public health. But let me first pause and talk about this term precision medicine. What do we mean by it? In fact it's a term that's just recently come into use. Like many new terms, it has different meanings to different people. and, I'm giving you a couple of definitions. One of them is from the UCSF website. Talking about precision medicine as the use of molecular tools. To make medicine more predictive, preventive and precise, those are important words to have in mind as we think about what precision medicine can do, and what challenges it might bring. Another definition on the web. Emphasizes that the patient is at the center of precision medicine, and also notes that precision medicine is not just genomic information or molecular information. But also other information including environmental data, that might be relevant to a patient's health care. and, and, this definition of precision medicine, I think, starts from, an important base. Which is that information is really at the center of healthcare. we, as we deliver healthcare, as we take care of patients. As we deliver public health interventions. We start by gathering information to help figure out what to do. We base interventions on the information that we gather and then when we implement an intervention, we gather information to figure out how it worked. So the premise of precision medicine is really a premise about more precise information. In order to enable us to do more and do better. And at the heart of it is a, an amazing technologic development, which is the ability to gather information about people's whole genomes and whole exomes. So whole genome is the full DNA sequence of an individual. We now have relatively efficient and cost effective methods to gather that information.
A whole exome simply refers to
the subset within the genome which is the protein coding genes. So, the technical ability to gather this information delivers to clinicians a huge additional amount of information that was previously not available. And drives a lot of the thinking about this new opportunity. And there are related molecular opportunities. We now can measure gene expression profiles and increasingly, we have the ability to do proteomic measurements, that is measuring proteins in the body and, and also a wide range of other metabolites. So we're on the cusp of technical opp, opportunities to gather huge amounts of information and to use them in clinical care. And the question is, how do we use that information in ways that enhance our ability, and what kinds of challenges, might this information pose? So, we're going to start by thinking about how we use genetics now. And I'm going to start with a story, and this is a story of a young boy. Who has vision bli, vision loss. He started with night blindness. Great inability to see, at nighttime. And his vision loss has steadily progressed. He's still a young boy. He's gone to the ophthalmologist. And the ophthalmologist has done a very careful eye exam. And has found out that he has a retinal degenerative condition called retinitis pigmentosa. This is an interesting condition, determined by genes. People who have variations in multiple different genes can develop this retinal degenerative condition. And in terms of the genetics of retina, retinitis pigmentosa more than 40 genes are involved. And one of the really interesting things about that, those many genes are, that are involved, is that they present in a variety of different inheritance patterns. So we have retinitis pigmentosa inherited as an X-linked recessive, in which moms are carriers and can pass on to affected sons. We have autosomal dominant forms, in which the inheritance goes from parent to child.
And we have autosomal recessive forms,
in which two parents are carriers, but can pass on this state to their children. And genetic testing now can help us to sort out for any given person whose exam tells us that ret, retinitis pigmentosa is present. What kind of inheritance pre, pattern is present in that family. And we'll talk why that matters, in fact, for the boy we're concerned about who has vision loss, genetic testing reveals he has a mutation in the RPGR gene. And that tells us he has X-linked retinitis pigmentosa. And in fact his family history confirms that. We see from his family history that there was an uncle who had the same condition, his mother is a carrier, and has passed this condition on to him. Why does it matter that he has X-linked retinitis pigmentosa? Well, it turns out this, this information is very useful prognostically. People with, retinitis pigmentosa can have a wide range of severity. And a wide range of time course for their loss of vision. Some people, only notice bothersome vision loss in their 30's and 40's. But other people can have very severe vision loss. And in fact, X-linked retinitis pigmentosa is on the severe end of the spectrum. Knowing that he has this form of retinitis pigmentosa, based on the genetic test result, we're able to predict that he is going to be legally blind by the time he's 20. We don't, unfortunately, have any treatment that will change the course of his vision loss. But the information can be useful in a variety of ways. First of all, it helps to know this in terms of his education plan, in terms of his career planning. This is someone who wants to plan for a career that will not be dependent upon vision. He may want to be sure that he lives in an urban environment where services will the there, available to him as a, a vision impaired individual. So the information has a lot of value to him socially and to his family. And also because he knows what he has, he can use that knowledge to find others with similar problems perhaps.
Have opportunities for support and for
sharing experience, so this is where a lot of medical genetics is. We can identify what the genetic problem is, we can help people to plan for the future. We have only limited abilities to change the course of the disease, never the less the genetic information can be helpful. And sometimes it can be a little more than information so a very common use of genetic testing nowadays is to assess inherited cancer risk. And I'm showing you here a family that represents what we call hereditary breast, ovarian cancer, a particular condition associated with mutations in the BRCA1, and BRCA2 genes. Here we have a family where the grandmother died of ovarian cancer the mother has breast cancer and, and developed it in her 40's and she now has a daughter who's had breast cancer in her 30's. This is a situation in which genetic testing is reasonable. To see whether a BRCA1, or BRCA2 mutation is present. And then to council the family accordingly. There are a lot of reasons why it might be useful to know if a BRCA1 mutation is, or BRCA2 mutation is, is present. First of all for the young woman who's just been diagnosed with breast cancer in her 30s, her treatment options might change, and she might make different choices about her treatment options, knowing about her risk. If she has a BRCA1 mutation, she's got a lifetime risk of breast cancer, of, of a second breast cancer, that's somewhere in the 40 to 50% range after having had her first breast cancer diagnosis. And that may be a reason to choose bilateral mastectomy, in the course of her breast cancer treatment, rather than lumpectomy or, mastectomy of just the affected breast. She may also want to consider oophorectomy. She has a 40% to 60% lifetime risk of ovarian cancer. And then there are some very exciting, data suggesting that there may be a particular set of medications called, PARP inhibitors.
That may have particular value,
in women, with these kinds of cancers. That's still under study, but there are very promising results. The information is equally, if not more significant, for her two sisters. Who are not affected with cancer at this time. If their sister has a BRCA1 mutation, they've got a 50/50 chance of having one themselves. And if they have inherited the breast cancer gene in the family. They have a variety of preventive options that they may want to consider. Again, prophylactic surgery, early breast screening with MRI and possibly chemoprevention with tamoxifen. All of these may help to reduce their cancer risks. So here we begin to see genetic testing. Enabling us to not just give people information that may be useful in planning, but actually to help guide treatment for the problems that they face. When we think about that family, with a very high rate of cancer and likelihood of inherited risk of breast cancer, we of course, also have to think about other genetic causes, not just BRCA1, and BRCA2. Part of the task of medical genetics in fact, is recognizing the range of genetic causes that might contribute to a particular health problem. In the case of breast cancer, we have at least three other inherited forms of cancer, where breast cancer's part of the picture. There's a syndrome called Li-Fraumeni Syndrome, in which people have, tend to have multiple cancers, breast cancer being one of them. There's a condition called Cowden Syndrome, that can cause early breast cancer. There's a condition called Lynch Syndrome, inherited colorectal cancer, but sometimes family members get breast cancer as well. And so part of the opportunity that new genomic technology gives us, is the possibility to look not just at the BRCA1 or BRCA2 gene. But in a single test to look at many genes to find and test for multiple different contributors to cancer risk, all with the same test. That's a, just a beginning of the opportunities that whole genome and
whole exome testing gives us.
But as the research has gone forward in breast cancer genetics, what we know is that in addition to the, the conditions I'm mentioning to you were high risks of cancer, are part of the picture. We are now finding many genes, many variations in those genes, that seem to be associated with small increase risk of breast cancer, or decrease risk of breast cancer. It looks like 40, 50, or more genes may contribute in some way to breast cancer risk. Most of them with a very small additive contribution. And one of the questions that we face as we increasingly gather this information is, what's the level of risk information that's useful? In general, in genetics, we want to pick all of the risk factors that are at the top of the triangle. Those risk factors that are what we call highly penetrant. There's a high likelihood that if you have a gene variant you're going to have a problem. Perhaps we want those moderately pren, penetrant genes where there's a significant risk, but do we want to go all the way down to the base? Do we want to find out if we're a little bit above average or a little bit below average for breast cancer risk or for any other risk? The new technologies pose this question, we're going to have to answer it. We're going to have to figure out what level of risk is useful.