Thuy Vu, M.S.
Genetic Counselor
Clinical Cancer Genetics
The University of Texas, MD Anderson Cancer Center
Hi, my name is Thuy Vu. I am a Genetic Counselor in a Clinical Cancer Genetics Program at MD Anderson Cancer Center. This lesson will focus on cancer genetic risk assessment.
At the end of this lesson, I hope that you should be able to identify some family history features suggestive for hereditary cancer syndromes; to understand what it means for an individual and their family to have hereditary cancer; and also to understand the benefits, limitations, and risks of genetic testing for hereditary cancer.
With hereditary cancers, I actually focus on a very small subset of all individuals who develop cancer. That is because the majority of individuals who develop cancer, it is due to sporadic causes or due to personal risk factors, and that accounts for about 70% to 80% of cancers. There are about 15% to 20% of cancers that are attributed to multifactorial inheritance, which is also called familial clustering. In these families, we see that there are multiple --- several individuals with cancer; however, they are diagnosed at later more typical ages of onset and there is really no clear pattern of inheritance in these families. With multifactorial cancers, it is due to a combination of environmental factors as well as some low penetrance or more subtle acting genetic factors. Finally, only 5% to 10% of cancers are actually attributed to inherited or genetic causes. In these families, we see that there are very young ages of cancer onset in the family, they occur in multiple family members, and it can have quite a significant impact on these families. So this is what the talk will focus on today.
With the discovery of hereditary cancer genes, genetic testing has become a valuable tool to identify patients at high risk for certain types of cancers. Therefore, as health care providers, it is your job to inquire about family cancer history, to identify red flags within the family history, and finally to refer these individuals and their families to genetic counseling and testing.
We will first talk about identifying the family history features.
As providers, it is important to take a cancer focused family history. This entails asking questions about three generations of the family, to focus on both the maternal and paternal side of the family. And for all individuals diagnosed with cancer it is important to ask about the type of cancers these individuals were diagnosed with, their ages at onset as well as any personal risk factors that may have contributed to that cancer. And for unaffected relatives, it is important to know the ages at death or the current ages of these individuals.
The majority of hereditary cancer syndromes are inherited in a family in an autosomal dominant manner with incomplete penetrance. With autosomal-dominant inheritance, we see that there are multiple generations affected and that the gene mutation that occurs within the family is passed out in a 50-50 manner. Men and women are equally affected, or at risk to inherit the mutation, and they are at equal risk to pass on the mutation to their sons or their daughters. The gene mutation does not skip generations, but due to incomplete penetrance, the cancer risk don't always occur in each individual who carries a genetic mutation. You can see here that the individuals shaded in orange have cancer history and have the gene mutation; whereas these individuals in the white and with the blue line down the middle, these individuals have the genetic mutation, but have not inherited cancer risk. So this individual here has not developed cancer, but several of their children have developed cancer and you can understand that this is an autosomal-dominant inheritance of this cancer genetic gene.
Alfred Knudson in 1971 described this Two-Hit Hypotheses in families with heritable retinoblastoma. The Two-Hit Hypothesis is the premise behind hereditary cancers in the sense that individuals with hereditary cancers inherit their first genetic mutation from a parent or through the germline and then the second mutation occurs in the normal allele is a somatic hit or is an acquired mutation. This is in contrast to individuals who have sporadic cancers. These individuals are born with two normal copies of the gene and acquire a somatic hit within one of the genes. And, therefore, individuals with sporadic cancers tend to develop their cancers at later ages of onset compared to families or individuals with hereditary cancers.
After you have taken the family history of cancer, these are some of the red flags that you should look for to identify families that might be suspicious or concerning to have a hereditary cancer syndrome. In these families, we would see that there are close relatives with a same type or related types of cancers and they all occur on the same side of the family. The majority of these individuals are diagnosed with cancers at much younger ages than you would expect to see that cancer occurring. You may see individuals with two or more primary cancers. In organs, where there are paired organs, there may be bilateral cancer involvement or multifocal tumors. Also autosomal-dominant inheritance is seen in these family histories. And if you are familiar with some of the cancer genetic syndromes, you may recognize that the family pattern is consistent with that particular genetic syndrome.
So now we will review some of the common hereditary cancer syndromes.
There are over two dozen hereditary cancer predisposition syndromes, but the three that I have listed on this page here are the ones that occur most commonly and the ones that some of you may be more familiar with. Amongst the hereditary breast cancer syndromes, the one that most people are familiar with is called Hereditary Breast and Ovarian Cancer Syndrome and this condition is associated with mutations within the BRCA1 and BRCA2 genes. For hereditary colorectal cancer syndromes, most individuals are familiar with two particular conditions. One is called Lynch syndrome, which was previously known as Hereditary Nonpolyposis Colorectal Cancer or HNPCC, and this condition is associated with mutations in the DNA mismatch repair genes. And the second hereditary colorectal cancer syndrome is called Familial Adenomatous Polyposis or FAP in short and this condition is associated with mutations in the APC gene. There are numerous other hereditary cancer syndromes as well, but we will not focus on that.
We will focus mostly on one particular hereditary form of cancer and that is called Hereditary Breast and Ovarian Cancer Syndrome. This condition accounts for the majority of hereditary breast cancers that occur and the condition is associated with mutations within the BRCA1 and BRCA2 genes.
For individuals, who carry a mutation in either one of these genes, the cancer risks are very high. For a woman who has a mutation with an either BRCA1 or BRCA2 genes, her lifetime risk to develop breast cancer increases up to 50% to 85%. And once the woman has developed a breast cancer, she has a high risk to develop a second primary breast cancer and that risk is 40% to 60% lifetime risk. This condition is also associated with ovarian cancer, which can include a fallopian tube and primary peritoneal cancers; and the lifetime risk is approximately 15% to 45% risk. We do see other cancers are associated with this condition and that includes men having breast cancer, prostate cancer as well as pancreas cancer.
Family history features that are concerning for Hereditary Breast and Ovarian Cancer Syndrome include multiple family members with ovarian or breast cancer. And typically these breast cancers occur at younger age of onset, so you would see many women with premenopausal onset of breast cancer. Women may also have bilateral breast cancer within their lifetime or you may see a woman with both bilateral and ovarian cancer within her lifetime. Individuals of Ashkenazi Jewish descent are considered to have a higher chance of having a mutation in one of these genes than non-Ashkenazi Jewish Caucasians. And male breast cancer is quite rare, but it is common in this particular condition.
This is a family history that exemplifies a typical family that may have a BRCA1 or BRCA2 gene. So you can see here in this first generation there are several women affected with breast cancer and ovarian cancer. This particular woman here, she has a BRCA1 mutation, but she has never developed cancer in her lifetime. And that may be due to the fact that she had a complete abdominal hysterectomy and oophorectomy when she was 46 years old. But we will presume that she has the mutation because her daughter was diagnosed with breast cancer at age 59 and does have the BRCA1 mutation. So this is an example of incomplete penetrance for hereditary cancer. You can see here this woman was diagnosed with breast cancer at age 52. She passed the mutation onto her son, who has not developed any cancer history. But his daughter developed breast cancer when she was 36 years old; and this man's sister had both breast cancer and ovarian cancer. So this family exemplifies some of the typical family history features that we would see commonly in this condition.
For families that have this condition, we do recommend that they follow with high-risk cancer surveillance and management options. And these recommendations that I am discussing here are based on the National Comprehensive Cancer Network. For breast cancer, we recommend that women undergo increased surveillance. This would include mammogram plus breast MRI every 12 months, a clinical breast exam every six months and that the screening begins at age 25 years. Women may also consider tamoxifen chemoprevention as well as risk-reducing bilateral mastectomy. For ovarian cancer risk, although the surveillance has no proven benefit, we do recommend that women consider a transvaginal ultrasound and a CA125 blood serum marker performed every six months beginning at age 35. Oral contraceptives may be a chemopreventative option and some women may also consider risk-reducing bilateral salpingo-oophorectomy.
In summary, for families that have hereditary cancer, we do recognize that there are very unique family history features and they do follow the red flags for hereditary cancer that we previously discussed. These family members are recommended to undergo increased cancer surveillance and management. And typically this begins at younger ages and at much increased frequency compared to the general population and there is a range of management options for these family members. And often within the United States, there are high-risk cancer management clinics available to coordinate all of these high-risk screening.
Finally, we will review the genetic counseling and testing process.
Genetic counseling is a process of providing information about an inherited condition to an individual or their family, of also providing supportive counseling to the families and providing these families with resources.
So once you have done your part in identifying the appropriate family history features that are concerning for hereditary cancer and have recommended a referral to genetic counseling for these families, they do see us for the genetic counseling and that includes a risk assessment of their family history. We will take a three-generation family history, focus on clarifying the reported cancer histories, as well as looking at all the individuals who have not developed cancer. From the risk assessment, we will identify whether genetic testing is appropriate for the family to consider, and importantly identifying who in the family is the most important person to initiate the genetic testing process. If genetic testing is pursued in the family, we will discuss interpretation of the genetic test results and also we will discuss psychosocial and insurance issues surrounding the genetic counseling and genetic testing process. And whether testing is pursued or not, we discuss individualized screening recommendations based on the family history.
The genetic testing process is a multistep process. The first step is that we need to identify who is at risk for having --- potentially having this hereditary cancer syndrome. Now not all patients seen for the genetic risk assessment are actually offered genetic testing. It is important to identify the most informative family member. Once genetic testing is discussed with the family, we want to provide very detailed pre-test information --- pretest counseling providing informed consent to the family or the individual undergoing testing. And then once the results are disclosed to the patient, provide detailed post test counseling and followup regarding management.
The American Society of Clinical Oncology has issued a policy statement back in 2003 based on recommending indications for genetic testing for cancer susceptibility and there are three premises to their recommendation. The first is that the personal or family history actually is suggestive for a particular hereditary cancer syndrome; that the tests being offered can be adequately interpreted; and that the results of the testing will actually aid in the diagnosis or medical management for that individual or their family. An important emphasis is that the genetic testing should always be done in the setting of post- [I am sorry] --- in the setting of pre- and post-test counseling.
Other considerations regarding genetic testing that families consider is that there is quite a wide range of possible emotional reactions for the patient as well as members of their family. It is important to ask the family, "How do they intend on using this information?" The patient or the person undergoing the genetic testing. "How do they intend to share this information with the rest of their family members?" And to focus on how the genetic test results may change their cancer screening and health management. So this will provide a lot of useful information for their health care team. Many patients also want to know the more logistical aspects of genetic testing such as the costs involved, the timeframe to receive the results, and the majority of patients do express concerns about genetic discrimination and we have a lot of resources that we can share with the families.
Some of the benefits of genetic testing include the ability to provide information to clarify one's cancer risk, to help determine the cancer risk for their family members. And this is a big motivation for many individuals to undergo genetic testing and counseling. The genetic test results may also aid in making decisions about cancer screening or management. Many families, they experience a sense of relief from uncertainty once the hereditary syndrome has actually been identified in the family or the genetic testing has ruled out that they have not inherited this cancer susceptibility gene. And finally, genetic testing may identify individuals who are not at high risk in families with no mutations and this definitely provides a great sense of relief from knowing that they are not at high risk for certain types of cancers.
Unfortunately, there are some limitations to genetic testing. The testing cannot determine with certainty if or when a cancer will develop and this goes back to the incomplete penetrance that we discussed earlier. A negative genetic test result cannot actually rule out an increased cancer risk. And we will talk about the implications and interpretation of genetic test results in a bit. Screening and prevention measures are not 100% effective and all individuals must be reminded that we all have a background risk for cancer development.
So, some of the basic concepts of genetic testing include the type of genetic test that would be offered to the family. There are several types including full gene analysis, known mutation testing, and Multi-Site testing. For full gene analysis, this involves analyzing the entire gene for mutations. Some of the limitations of this are that not all mutations are identifiable with today's current genetic testing technology. And also we may identify variants or genetic alterations that have uncertain clinical significance. And this can be quite frustrating for the genetic provider as well as the patient and their family. However, once the mutation has been identified in the family, then at-risk relatives can undergo what is called known mutation testing and this is testing for a mutation that has previously been identified in the family. This is actually the best method once the mutation is found in the family because it provides 100% accuracy whether an individual has inherited the genetic susceptibility gene or not. For some genetic testing, we actually initiate the testing process with what is called Multi-Site testing and this is testing for a panel of specific mutations. I mentioned earlier that one of the red flags for Hereditary Breast and Ovarian Cancer Syndrome is that an individual of Ashkenazi Jewish descent may have a high risk of having a BRCA1 and BRCA2 gene change. For these individuals, we would actually offer Multi-Site testing for the three Ashkenazi Jewish founder mutations.
Once an individual pursues genetic testing, there are several types of results that can be anticipated. The first type of result is called a positive result. This means that a deleterious or disease-causing mutation has been identified in the family. This really means that -- this confirms the diagnosis that the family has this particular hereditary cancer syndrome. And having a positive result allows family members to definitively clarify whether they have inherited the condition or not and they can then pursue the known mutation testing. Another type of result we can expect to receive is called a true negative result. True negative results can be anticipated in individuals who pursue known mutation testing. This is because they are testing only for that mutation that has already been identified in the family and they have tested negative for this. So, we know that they have truly not inherited this gene for cancer susceptibility and this is a very reassuring result for the individual. And these individuals have the same cancer risk as anyone else in the general population now.
These two types of results have a little bit more ambiguity in interpretation and it is important to return to the family history to help interpret these results. An uninformative negative result can be received when --- [I am sorry] --- full gene mutation testing is pursued. With uninformed negative results, it means that no mutation has previously been identified in the family and this person has tested also negative for any mutations in that gene. So in these cases the family mutation still cannot be ruled out. Oftentimes, we return to the family history to see if there is a better, more informative test candidate or a family member that could undergo the same genetic testing. And the cancer risk management is based back on the family history and the pattern of cancers that we see. The last type of result we may anticipate receiving is called an uncertain variant. This means that a DNA change or alteration was identified from the genetic testing, but the clinical significance is unknown. In this case, testing affected family members only, can help determine whether the gene mutation or gene alteration is segregating with cancer. But there is no utility in testing unaffected family members because we do not know how to interpret these results. The cancer risk management is, therefore, based on the family history of cancer.
Regardless of whether the patient pursues genetic testing, risk management options for cancer are always discussed. We provided detailed individualized cancer screening and a prevention plan based on review of the three-generation family history and we discuss medical management options including referrals to appropriate specialists. So, while some families may not actually have a gene mutation identified in the family, the family history features may be still concerning for hereditary cancer and a referral to high-risk screening clinics may still be indicated for the family.
Many families are very concerned about the possibility of genetic discrimination. In 2008, Congress passed a law called Genetic Information Nondiscrimination Act. This is also known as GINA. And GINA prohibits discrimination in health coverage and employment based on genetic information. Genetic information is defined as an individual or their family members' genetic test results, their family history alone, and information obtained from the genetic testing, counseling, or education process by a family member. To learn more about GINA, you can go to this link listed at the bottom of the page.
Prior to the passage of GINA in 2008, approximately 47 states have passed laws pertaining to genetic discrimination. These states had variable protections for the requirement of genetic test and information, eligibility and risk classification by health --- group health insurers. And states --- now with the passage of GINA, states that had less protection than GINA will actually need to comply with minimum protections of GINA. So this can be good news for families in which you have family members scattered all across the United States because GINA provides a blanket law regardless of where you live in or if you plan on moving to other states. To actually learn about your specific state laws, you can to go the National Conference of State Legislatures and look up more information on that.
In summary, not everyone who presents for genetic counseling will actually be offered genetic testing. The genetic counseling process focuses on providing both pre- and post-test genetic counseling. Not all genetic test results are considered unequivocal. We often have to return to the family history for interpretation of these results and also make cancer risk management recommendations based on either the family history or whether a positive genetic test result has been identified in the family. With the genetic counseling and genetic testing process, it is very important to consider the emotional and psychological impacts on the family; as different family members will perceive these results in very different ways. And finally there are federal and state legislation for genetic discrimination.
In summary, there are many concerning family histories that we have discussed today. And if you have identified a family that meets any of these red flags for hereditary cancer, please make a referral for genetic counseling for these individuals. This will include families with young onset of cancer, multiple affected family members occurring in multiple generations, and individuals with bilateral multifocal or multiple primary cancers. The genetic consultation visit is a risk assessment of an individual's personal, medical, and family histories for hereditary cancer syndrome. And although patients may undergo genetic counseling, genetic testing may not always be recommended for that individual or their family and, therefore, it may not be appropriate for everyone. Whether testing is discussed or pursued by the patient, implications for increased screening and cancer risk management are always discussed based on the family cancer pattern. This concludes my presentation. Thank you for your time.
Cancer Genetic Risk Assessment video
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