1 00:00:01,053 --> 00:00:05,930 [BLANK_AUDIO]. 2 00:00:05,930 --> 00:00:09,280 Next I'd like to talk about hereditary cancers. 3 00:00:09,280 --> 00:00:11,770 So we know that cancer is a genetic disease. 4 00:00:11,770 --> 00:00:13,480 It's always a genetic disease. 5 00:00:13,480 --> 00:00:16,680 It involves mutations that occur at the level of DNA. 6 00:00:16,680 --> 00:00:21,230 But these mutations are ones that occur at the level of an individual cell. 7 00:00:21,230 --> 00:00:27,460 They're called somatic mutations, but some cancers are, in fact, inherited. 8 00:00:27,460 --> 00:00:31,380 They're caused by mutations that occur in the germ cells, so the sperm or the egg, 9 00:00:31,380 --> 00:00:33,750 and those are passed down, so a person 10 00:00:33,750 --> 00:00:37,550 starts with a cell that already has a mutation. 11 00:00:37,550 --> 00:00:41,099 But additional mutations are then acquired in 12 00:00:41,099 --> 00:00:44,830 an individual cell to ultimately cause cancer. 13 00:00:46,000 --> 00:00:49,680 So while all cancer is genetic, not all cancer is hereditary. 14 00:00:50,950 --> 00:00:53,930 So what do we know about the heritability of cancers? 15 00:00:53,930 --> 00:00:58,840 Well, we know that some cancers run in families and others not so much. 16 00:00:58,840 --> 00:01:00,120 One of the ways that we measure 17 00:01:00,120 --> 00:01:03,960 heritability is through a familial recurrence risk. 18 00:01:03,960 --> 00:01:08,320 What we do there is ask for a patient who has cancer. 19 00:01:08,320 --> 00:01:11,422 What is the risk that their sibling also has cancer, and 20 00:01:11,422 --> 00:01:15,380 how does that compared to the risk in that average population. 21 00:01:15,380 --> 00:01:17,612 We take a ratio of that risk to the sibling, 22 00:01:17,612 --> 00:01:20,960 and the risk in the general population, and that's the sibling 23 00:01:20,960 --> 00:01:23,626 recurrence risk in this case, but you could use any 24 00:01:23,626 --> 00:01:27,310 other family members and that would be a Familial Recurrence Risk. 25 00:01:28,560 --> 00:01:34,750 This one study by Risch in 2001 looked at the Familial Risk of Cancer. 26 00:01:34,750 --> 00:01:38,110 From two different sets of families, and I have those plotted out here. 27 00:01:39,150 --> 00:01:42,270 There were some commonalities between the two groups 28 00:01:42,270 --> 00:01:44,870 of families, but other places where they differed. 29 00:01:44,870 --> 00:01:47,250 A couple things I wanted to point out. 30 00:01:47,250 --> 00:01:49,970 For example, testicular cancer shows a very high 31 00:01:49,970 --> 00:01:53,840 familial recurrence risk in both sets of families. 32 00:01:53,840 --> 00:01:57,420 But for other cancers, there's not such great concordance. 33 00:01:57,420 --> 00:02:01,580 One disease that we know has a familial nature is breast cancer. 34 00:02:01,580 --> 00:02:04,730 And the studies show a two to four-fold increased 35 00:02:04,730 --> 00:02:08,770 risk to siblings of patients who have familial breast cancer. 36 00:02:13,050 --> 00:02:18,810 So speaking of familial disease, I want to next talk about family history 37 00:02:18,810 --> 00:02:24,140 and how and when we consider taking a family history of patients and 38 00:02:24,140 --> 00:02:30,280 how that relates to breast and colon cancer in particular. 39 00:02:30,280 --> 00:02:32,250 So when we talk about family history 40 00:02:32,250 --> 00:02:35,980 of cancer, we usually take those at diagnosis. 41 00:02:35,980 --> 00:02:38,392 So here's a family and here's our patient 42 00:02:38,392 --> 00:02:40,938 if they were diagnosed with cancer, we would 43 00:02:40,938 --> 00:02:43,149 want to get a complete family history at 44 00:02:43,149 --> 00:02:46,770 that point, and then update it regularly over time. 45 00:02:46,770 --> 00:02:49,572 We would like to ask about first and second-degree relatives. 46 00:02:49,572 --> 00:02:54,050 First-degree relatives being siblings parents and 47 00:02:54,050 --> 00:02:56,060 any offspring that they might have. 48 00:02:56,060 --> 00:03:00,470 But, history in extended relatives, as well, such as grandparents, aunts 49 00:03:00,470 --> 00:03:04,550 and uncles and cousins, is also going to be important, so. 50 00:03:04,550 --> 00:03:09,640 Asking about cancer in both first degree and second degree relatives is key. 51 00:03:09,640 --> 00:03:13,020 And then for each of those family members 52 00:03:13,020 --> 00:03:16,870 who have cancer, such as shown here, we would 53 00:03:16,870 --> 00:03:19,880 want to determine what was the primary type of 54 00:03:19,880 --> 00:03:23,820 cancer, what was their age at diagnosis, the lineage. 55 00:03:23,820 --> 00:03:28,120 So you want to know if it came from the maternal side or the paternal side. 56 00:03:28,120 --> 00:03:30,395 The ethnicity, because some cancers are 57 00:03:30,395 --> 00:03:32,800 more common in different ethnic groups such 58 00:03:32,800 --> 00:03:35,465 as Ashkenazi Jewish population has an increased 59 00:03:35,465 --> 00:03:38,580 risk of breast cancer from BRCA1 mutations. 60 00:03:38,580 --> 00:03:42,960 And finally, the results of any genetic testing that was done in that family. 61 00:03:47,110 --> 00:03:51,335 So how will we recognize a hereditary cancer? 62 00:03:51,335 --> 00:03:53,447 Well, if you think about an individual 63 00:03:53,447 --> 00:03:56,135 patient, some of the characteristics that might 64 00:03:56,135 --> 00:04:00,810 lead you to think that there is a familiar or hereditary basis for the cancer. 65 00:04:00,810 --> 00:04:05,970 Is if they have multiple primary tumors in the same organ, or different organs. 66 00:04:05,970 --> 00:04:09,846 So different cells have become mutated at different times, 67 00:04:09,846 --> 00:04:14,940 and generated the two distinct, two or more distinct cancers. 68 00:04:14,940 --> 00:04:18,630 Another clue might be bilateral primary tumors, 69 00:04:18,630 --> 00:04:20,720 such as in the case with breast cancer. 70 00:04:20,720 --> 00:04:25,520 If you have a tumor that originates in both breasts 71 00:04:25,520 --> 00:04:30,280 independently, that's an indication that this might be an inherited cancer. 72 00:04:30,280 --> 00:04:33,510 A younger than usual age of onset for a tumor diagnosis 73 00:04:33,510 --> 00:04:37,430 is also one of the keys that a cancer might be genetic. 74 00:04:37,430 --> 00:04:39,266 If you have a tumor that has a rare 75 00:04:39,266 --> 00:04:43,414 histology that's not very, very commonly noticed that might also 76 00:04:43,414 --> 00:04:47,018 be some indication that there's a genetic component, as well 77 00:04:47,018 --> 00:04:50,410 as tumors that occurs in the sex not usually affected. 78 00:04:50,410 --> 00:04:54,770 Think about breast cancer that occurs in males, which is possible, 79 00:04:54,770 --> 00:05:00,250 that's some indication that that may be a genetic or inherited cancer. 80 00:05:00,250 --> 00:05:03,242 And then when you look at the patient's family, you 81 00:05:03,242 --> 00:05:07,410 want to look for first degree relatives with the same tumor history. 82 00:05:07,410 --> 00:05:09,700 So all of these are clues, they're red flags, 83 00:05:09,700 --> 00:05:12,430 that you may be looking at an inherited cancer. 84 00:05:15,360 --> 00:05:17,590 So I'm going to talk briefly about the 85 00:05:17,590 --> 00:05:19,930 hereditary basis of two cancers, breast cancer 86 00:05:19,930 --> 00:05:24,440 and colon cancer, since those are the ones that we've made the most progress on. 87 00:05:24,440 --> 00:05:30,665 If you think about breast cancer the risk is about 1 in, 1 in 10 so about a 12, 1 88 00:05:30,665 --> 00:05:37,690 in 9 or 10, about a 10 or 12% chance of developing breast cancer in your life. 89 00:05:37,690 --> 00:05:40,260 And first degree family history of breast 90 00:05:40,260 --> 00:05:42,980 cancer actually increases your risk about two fold. 91 00:05:44,000 --> 00:05:48,240 Now, only about 5 to 10% of breast cancer is hereditary. 92 00:05:48,240 --> 00:05:53,350 So in other words, most breast cancer, 90% of breast cancer is sporadic. 93 00:05:53,350 --> 00:05:55,400 Having a family history will not tell you anything. 94 00:05:56,860 --> 00:05:58,390 What do we know about the inheritance? 95 00:05:58,390 --> 00:06:01,580 Well, we know a lot more than we know about other cancers. 96 00:06:01,580 --> 00:06:06,880 We know that the inheritance of breast cancer, it acts as a complex disease. 97 00:06:06,880 --> 00:06:10,895 We've talked a lot about complex diseases and how there are genes 98 00:06:10,895 --> 00:06:16,100 and there are environmental factors that cause the cancer, and cause the disease. 99 00:06:16,100 --> 00:06:17,930 And that's true for breast cancer, as well. 100 00:06:17,930 --> 00:06:21,690 But there are forms of breast cancer that appear to act in 101 00:06:21,690 --> 00:06:27,510 a Mendelian fashion, such as those due to mutations in BRCA1 and BRCA2. 102 00:06:27,510 --> 00:06:32,922 These are genes that are indicative of hereditary breast and ovarian 103 00:06:32,922 --> 00:06:38,450 cancer, but those aren't the only genes involved in breast cancer. 104 00:06:38,450 --> 00:06:43,820 If you look at what we know about the genetics of breast cancer, we still 105 00:06:43,820 --> 00:06:48,960 are unable to explain about half of the hereditary basis of breast cancer. 106 00:06:50,130 --> 00:06:56,280 The BRCA1 and 2 genes account for only about 15% of inherited breast cancer. 107 00:06:56,280 --> 00:07:02,320 Then we have mutations in other genes that behave in a Mendelian fashion. 108 00:07:02,320 --> 00:07:05,840 Parts of cancer syndromes were breast cancers manifestation. 109 00:07:05,840 --> 00:07:09,836 And then we have other polymorphisms that have come out of genome 110 00:07:09,836 --> 00:07:12,574 mod asssociation studies where they confer 111 00:07:12,574 --> 00:07:16,050 a slightly increased risk of breast cancer. 112 00:07:16,050 --> 00:07:18,770 So, all of this together gives you a good picture 113 00:07:18,770 --> 00:07:21,900 of what we know about the genetics of hereditary breast cancer. 114 00:07:25,240 --> 00:07:26,970 What about hereditary colon cancer? 115 00:07:26,970 --> 00:07:29,750 Well, we know that a family history of colon 116 00:07:29,750 --> 00:07:34,230 cancer increases a patient's risk about two- to fourfold. 117 00:07:34,230 --> 00:07:35,870 There are a couple of different types 118 00:07:35,870 --> 00:07:39,230 of hereditary colon cancer that have been described. 119 00:07:39,230 --> 00:07:44,710 One of them is familial adenomatous polyposis or FAP for short. 120 00:07:44,710 --> 00:07:47,734 You can see the histology of the cancer 121 00:07:47,734 --> 00:07:51,400 here or what, what the colon actually looks like. 122 00:07:51,400 --> 00:07:55,830 These people have hundreds and hundreds of polyps that occur along their colon. 123 00:07:55,830 --> 00:08:00,110 And the chance is high that at least one of these will turn cancerous. 124 00:08:00,110 --> 00:08:03,050 This disease is due to mutations in a gene called APC. 125 00:08:04,400 --> 00:08:09,710 There is another type of hereditary colon cancer called HNPCC, which 126 00:08:09,710 --> 00:08:15,200 is also called Lynch Syndrome, and this is due to mutations in DNA repair 127 00:08:15,200 --> 00:08:22,070 enzymes specifically these DNA repair enzymes MLH1 and MSH2 and others. 128 00:08:22,070 --> 00:08:27,960 And when these are mutated, they cause non-polyposis type of cancer. 129 00:08:27,960 --> 00:08:32,550 This accounts for about 2 to 5% of the total burden of colorectal cancer. 130 00:08:32,550 --> 00:08:37,730 So these are two types of inherited colon cancer. 131 00:08:37,730 --> 00:08:42,760 And we're able to offer testing for these in the clinic as well. 132 00:08:42,760 --> 00:08:46,300 What do we know about the genes involved in inherited cancers? 133 00:08:46,300 --> 00:08:47,530 We know that some of these are 134 00:08:47,530 --> 00:08:50,740 tumor suppressor genes, and tumor suppressor genes 135 00:08:50,740 --> 00:08:56,330 act at the recessive level in a recessive fashion at the level of the cell. 136 00:08:56,330 --> 00:08:58,710 In other words, both copies of the gene need to 137 00:08:58,710 --> 00:09:00,900 be mutated in order for them to have an effect. 138 00:09:01,980 --> 00:09:04,108 But at the pedigree level or at the 139 00:09:04,108 --> 00:09:07,950 individual level, they act as a dominant trait. 140 00:09:07,950 --> 00:09:08,810 What do I mean by that? 141 00:09:08,810 --> 00:09:11,330 Well to explain this we have to look at 142 00:09:11,330 --> 00:09:16,260 this Knudson's two hit hypothesis for tumor suppressor genes. 143 00:09:16,260 --> 00:09:19,739 This hypothesis states that a cancer, a tumor suppressor 144 00:09:19,739 --> 00:09:22,934 gene requires two mutations and, and in a cancer, in 145 00:09:22,934 --> 00:09:26,129 a sporadic cancer as opposed to a familial one, these 146 00:09:26,129 --> 00:09:30,080 two mutations are acquired over the course of a lifetime. 147 00:09:30,080 --> 00:09:33,020 So you have your normal pair of chromosomes or 148 00:09:33,020 --> 00:09:36,460 normal set of, of the tumor suppressor gene, normal pair. 149 00:09:36,460 --> 00:09:41,132 And one copy of that gene becomes mutated and then at some later time the other 150 00:09:41,132 --> 00:09:43,760 gene becomes mutated so now both copies are 151 00:09:43,760 --> 00:09:47,480 mutated, and that allows the cancer to develop. 152 00:09:47,480 --> 00:09:52,530 What happens in an inherited cancer is you're born with one mutated copy already. 153 00:09:52,530 --> 00:09:55,455 So you go through your life only needing to acquire one 154 00:09:55,455 --> 00:10:00,240 additional mutation in that gene, and when that happens you develop cancer. 155 00:10:00,240 --> 00:10:02,550 And you can see how this explains why these 156 00:10:02,550 --> 00:10:05,086 cancers have an earlier age of onset as well. 157 00:10:05,086 --> 00:10:10,363 Okay. 158 00:10:10,363 --> 00:10:16,507 Besides inherited breast and colorectal cancer, there are also inherited 159 00:10:16,507 --> 00:10:22,590 familial cancer syndromes, and I have several of them listed here. 160 00:10:22,590 --> 00:10:26,733 These are syndromes where, you have one gene that's mutated. 161 00:10:26,733 --> 00:10:29,915 For example TP53, which leads to what's 162 00:10:29,915 --> 00:10:33,785 called Li-Fraumeni disease, which is an inherited 163 00:10:33,785 --> 00:10:37,139 cancer syndrome where family members can have 164 00:10:37,139 --> 00:10:40,204 any one of a number of different cancers. 165 00:10:40,204 --> 00:10:44,460 Leukemia, breast, brain, soft tissue cancers. 166 00:10:44,460 --> 00:10:47,270 So, in the pedigree, it's not a homogenous cancer. 167 00:10:49,450 --> 00:10:52,050 Here's an example of what a Li-Fraumeni pedigree looks like. 168 00:10:52,050 --> 00:10:56,330 And you can see the diversity of different cancers in that pedigree. 169 00:10:56,330 --> 00:10:58,660 Now you see a lot of cancer, which is your clue 170 00:10:58,660 --> 00:11:02,900 that this is an inherited cancer, but it is again diverse. 171 00:11:02,900 --> 00:11:04,972 The next few slides I'm going to provide you 172 00:11:04,972 --> 00:11:07,492 with some information, and it's quite detailed so I 173 00:11:07,492 --> 00:11:09,564 just wanted to mention a couple of things and 174 00:11:09,564 --> 00:11:12,180 you can look, look them over in your leisure. 175 00:11:12,180 --> 00:11:14,020 But, one of the things is when to seek 176 00:11:14,020 --> 00:11:17,250 genetic counselling even in the absence of a family history. 177 00:11:17,250 --> 00:11:22,362 There might be certain clinical situations where, for example, you have somebody 178 00:11:22,362 --> 00:11:27,930 who has a triple negative breast cancer, which I'll explain in subsequent slides. 179 00:11:27,930 --> 00:11:33,630 Or other characteristics of their cancer, which may lead you to suspect that this is 180 00:11:33,630 --> 00:11:39,160 indeed an inherited form of disease, even in the absence of family history. 181 00:11:39,160 --> 00:11:44,040 Similarly having rare tumors and pediatric cancers are all indications when 182 00:11:44,040 --> 00:11:47,380 you may want to seek the counsel of a genetics professional. 183 00:11:52,090 --> 00:11:55,276 There are also various risk assessment models that could be 184 00:11:55,276 --> 00:11:59,410 used to determine whether your patient should undergo genetic testing. 185 00:11:59,410 --> 00:12:00,870 And I have those listed here. 186 00:12:00,870 --> 00:12:04,260 Genetic tests are currently available for Lynch syndrome, 187 00:12:04,260 --> 00:12:08,618 the inherited colorectal cancer, inherited breast and ovarian cancer. 188 00:12:08,618 --> 00:12:12,989 Melanoma Li-Fraumeni, and Cowden, both cancer 189 00:12:12,989 --> 00:12:17,020 syndromes as well as some other tests. 190 00:12:17,020 --> 00:12:21,310 But there are, like I said, some risk assessment models that can be used ahead 191 00:12:21,310 --> 00:12:23,325 of time in order to determine whether 192 00:12:23,325 --> 00:12:26,010 your, your patient is a candidate for testing. 193 00:12:29,450 --> 00:12:31,290 And finally, I've provided you with 194 00:12:31,290 --> 00:12:34,800 some resources for locating cancer genetic specialists, 195 00:12:34,800 --> 00:12:38,210 a number of different websites that can be used to identify these people. 196 00:12:42,400 --> 00:12:45,960 And one last thing that I wanted to mention, if you decide to undergo 197 00:12:45,960 --> 00:12:49,300 genetic testing, for known cancer susceptibility genes, 198 00:12:49,300 --> 00:12:51,010 a couple things to keep in mind. 199 00:12:51,010 --> 00:12:53,470 First of all, a negative test result is 200 00:12:53,470 --> 00:12:56,460 no guarantee that the cancer will not develop. 201 00:12:56,460 --> 00:12:59,513 We already know that inherited cancers account for 202 00:12:59,513 --> 00:13:02,380 a very small portion portion of cancer burden. 203 00:13:02,380 --> 00:13:08,240 So the chances of a person developing cancer are still pretty much 204 00:13:08,240 --> 00:13:11,950 it, it as high as they were before you got the genetic testing. 205 00:13:11,950 --> 00:13:13,610 So, keep that in mind, it does not 206 00:13:13,610 --> 00:13:16,230 guarantee that you will not develop the cancer. 207 00:13:16,230 --> 00:13:21,710 Similarly, a positive test result is no guarantee that the cancer will develop. 208 00:13:21,710 --> 00:13:25,021 Early on when we discovered the breast cancer genes 209 00:13:25,021 --> 00:13:29,567 BRCA1 and BRCA2, they were discovered using high risk families. 210 00:13:29,567 --> 00:13:32,648 People who had pedigrees where there were 211 00:13:32,648 --> 00:13:36,756 multiple effected individuals and so the penetrance the 212 00:13:36,756 --> 00:13:39,600 probability of getting disease if you had a 213 00:13:39,600 --> 00:13:43,630 mutation, was actually estimated to be quite high. 214 00:13:43,630 --> 00:13:45,610 As high as 80% in your lifetime. 215 00:13:45,610 --> 00:13:47,518 But now, those estimates have come down, 216 00:13:47,518 --> 00:13:50,090 because we've been able to evaluate more people. 217 00:13:50,090 --> 00:13:53,750 We've taken different ascertainment strategies, and this has actually helped 218 00:13:53,750 --> 00:13:56,670 us to come up with more accurate estimates of risk. 219 00:13:56,670 --> 00:13:59,829 So, having a cancer predisposing mutation is 220 00:13:59,829 --> 00:14:02,890 no guarantee that you will develop cancer. 221 00:14:04,540 --> 00:14:07,010 Finally, what can you do if you have a mutation? 222 00:14:07,010 --> 00:14:09,803 Well, there's several risk management strategies that 223 00:14:09,803 --> 00:14:12,090 can be undertaken for a positive test. 224 00:14:12,090 --> 00:14:14,330 And again, using the breast cancer example. 225 00:14:14,330 --> 00:14:19,500 If you are positive for BRCA1, you can increase surveillance. 226 00:14:19,500 --> 00:14:22,830 In other words, do more mammograms and screening. 227 00:14:22,830 --> 00:14:25,430 There's also the possibility of initiating 228 00:14:25,430 --> 00:14:28,910 prophylactic hormone therapy, lifestyle changes, and 229 00:14:28,910 --> 00:14:32,920 we know diet and exercise can increase, or influence your risk of cancer. 230 00:14:32,920 --> 00:14:34,760 And finally, prophylactic surgeries. 231 00:14:34,760 --> 00:14:35,910 Prophylactic imogr, 232 00:14:38,120 --> 00:14:42,040 mastectomies, and a nephrectomies can help reduce your risk, of breast 233 00:14:42,040 --> 00:14:44,550 and ovarian cancer if you carry a mutation, in this gene. 234 00:14:46,190 --> 00:14:47,965 Now I have a question for you. 235 00:14:47,965 --> 00:14:54,742 Cancer is primarily due to which type of mutations, somatic or germline? 236 00:14:54,742 --> 00:14:58,198 The answer is the cancer is always a somatic disease, and only 5 237 00:14:58,198 --> 00:15:02,109 to 10% of cancers are inherited or due to mutations in the germline. 238 00:15:02,109 --> 00:15:12,109 [BLANK_AUDIO]