Defining HRD and its Role in Ovarian Cancer

Dr. Thomas Herzog: So Dr. Hagemanm, I'm going to have you start us off here and tell us about defining HRD and its role in ovarian cancer.

Dr. Ian Hagemann: Yeah, of course. It's well known that cancer is a disease of the cellular genome. And in fact, cells even under ordinary circumstances accumulate many mutations or DNA changes per day. Some of them are due to cellular processes, some of them due to environmental insults that they sustained. And so cells have naturally evolved mechanisms to repair all of these. We could talk through some of them. Some of the smaller forms of DNA damage can be repaired by just excising the nitrogenous base, or maybe a whole nucleotide. So bulky adducts of tobacco smoke, where a large molecule gets conjugated to DNA. The cell will clear out a short piece of single strand of DNA and put the correct strand back in. We need a different set of mechanisms to repair double stranded breaks in DNA that can happen due to a cosmic ray or some other process interacting adversely with the DNA. And the cells preferred mechanism for repairing these is to repair the DNA, so the sequence is unchanged. If there is a set of homologous chromosomes after DNA replication in an appropriate phase of the cell cycle, so in the phase where there two sister chromatids present homologous chromosomes, the second copy will be used as a template to repair the first and that's your homologous recombination pathway. There's a wide variety of genes, probably 15, 20 genes that assemble their protein products into an apparatus for homologous recombination. The second mechanism for repairing a double strand break is non-homologous end joining. That's very simple. The cell just sticks the two ends of the DNA back together and has to hope that it stuck the correct ones back together in the right order. So that's a very error prone process. So not surprisingly, it's very desirable for cells to have intact homologous recombination repair mechanisms. Unfortunately, mutations in the genes that are responsible for assembling that complex are not that uncommon in the gene pool. They're also not that uncommon to be acquired somatically by a cancer. So that's some of what we want to kind of talk about next. Mutation. So the most important genes in the homologous recombination repair pathway, the best known best characterized first discovered are BRCA1 and 2, or BRCA1 and BRCA2. Either of these genes can be mutated. Pretty common to see in high-grade serous ovarian cancer or other gynecologic cancers, other serous cancers of the GYN track. But we're really focusing on ovarian high-grade serous tumors here. Depending on the study that you look at, you'll see some variation in the rate of mutation in the BRCA1 or BRCA2 gene. But let's just say it's not rare. Somewhere around 10% of ovarian cancers are going to be related to a germline mutation in BRCA1 or BRCA2. So that will be a variant that was inherited from a parent and you might be able to detect segregation of that cancer predisposition trade in their pedigree if you were to take a family history and draw it out. Depending on not only what series you look at, but how you assay it. You might find higher or lower, but let's say somewhere around 1 in 10. And then besides that, it's not uncommon for serous ovarian cancers to have acquired a somatic mutation in this pathway. That's adaptive for the cancer cells. Because once that repair pathway is knocked out, the cells acquire additional mutations and some of them lead to a selective advantage for the tumor cells. So let's say somewhere in the neighborhood of another 20% of ovarian cancers are going to have a somatic mutation. Somewhere in this pathway, they'll have a deficiency in their ability to carry out homologous recombination repair. So we've summarized a couple of studies here on the slides, but I think that the exact numbers aren't as important as the takeaway points that, A, these variations can be either are coming from the germline. Of course, then they're in every cancer cell or can be acquired somatically. And, B, that they're not rare. C, that there's actually a number of genes that can be implicated, not only BRCA1 and BRCA2. But additional homologous recombination repair genes. So BRIP1, CHEK2, nibrin which is NBN, RAD51 complex components are all genes that can be mutated either in the germline or somatically and confer what we call a homologous recombination repair HRD phenotype on cancers. And if you look at ovarian cancer overall, again depending on your series, the majority will not be abnormal for HRD. Then you'll have a subset that have a germline deficit and then a subset that have a somatic inactivation of the HRD pathway.