Continuing Medical Education
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by Simone Weinmann, MS, CGC,
and Nancy Mills, MD
Introduction Cancer is one of the leading causes of death worldwide. Nearly 40% of the population will be
diagnosed with cancer in their lifetime.1 Breast, lung, and prostate cancers are the most common types. The average woman has a 12-13% chance of developing breast cancer; in other words, 1 out of every 8 women will develop breast cancer in her lifetime.[2]
Cancer is inherently a disease of abnormalities of genetic origin; the accumulation of genetic mutations causes cancer by affecting important cellular mechanisms involved in cell proliferation and apoptosis, leading to uncontrolled cell growth.3 Mutations may arise from endogenous errors in replication or exogenous agents such as radiation and chemical carcinogens. The activation of oncogenes, which typically stimulate cell proliferation, and the inactivation of tumor suppressor genes, which typically inhibit cell proliferation, both disturb cellular homeostasis and can lead to malignancy.[4]
Cancer can be sporadic or have a hereditary component. Only about five to ten percent of cancers are hereditary.[5] If cancer is inherently a disease of genetic abnormalities, it may seem paradoxical that only a small percentage of cancers occur on the basis of genetic inheritance.
The ”two-hit” hypothesis, tumorigenesis. Sporadic vs hereditary.
The “two-hit” hypothesis postulates that tumorigenesis requires two “hits”, or mutations, as humans have two copies, or alleles of most genes. The NIH defines tumorigenesis as the pathologic process that involves the transformation of normal cells to a neoplastic state resulting in polyclonal or monoclonal neoplastic cell proliferation. In sporadic cases of cancer, both of these mutational events are randomly acquired on the somatic level in the tumor over the course of someone’s lifetime. In hereditary cases of cancer, there is an inherited germline mutation already in place (from birth), so cells only need one more “hit” to trigger tumorigenesis.[6] These inherited mutations increase one’s risk of cancer compared to the general population, as only one additional mutation is necessary to allow the process of tumorigenesis to occur.
Germline pathogenic mutations are considered to be disease causing and are associated with an inherited cancer predisposition. These mutations are typically inherited in an autosomal dominant manner, so each child has a 50% chance of inheriting the cancer predisposition mutation from a parent. Therefore, if one person is found to have a germline mutation, their siblings, their children, and their parents each have a 50% chance of having the same genetic mutation.
The caveat here is that these mutations are not fully penetrant, meaning not everyone with an inherited mutation will develop cancer in their lifetime. This is thought to be due to the second hit (mutation) that needs to be acquired for cancer to develop. Sometimes this second hit never occurs, or it occurs in an organ type where the specific genetic defect does not substantially contribute to tumorigenesis. The exact science behind why specific genetic mutations increase certain cancer types is not fully understood at this time. Given this reduced penetrance, cancers and cancer risk can often give the appearance of “skipping a generation” as not everyone in each generation who carries the mutation will be affected with cancer.
Family History
Family history can be an underutilized tool when evaluating for hereditary cancer. An in- depth family history is indeed the backbone of a genetic counseling session and allows for proper risk assessment when evaluating for hereditary cancer syndromes. A hereditary cancer syndrome describes the range of cancers an individual may be at risk for if they are found to have a germline mutation.
A strong family history of cancer can be indicative of a familial germline mutation. Certain “red flags” in the family history that increase suspicion for a genetic predisposition to cancer include the following:
Young age of cancer diagnosis (<50 years old)
Multiple family members with the same type of cancer
Individuals with multiple primary cancers or for paired organs bilateral cancers (such as breast)
Rare cancers (such as male breast cancer, ovarian cancer, pancreatic cancer, or medullary thyroid cancer)
Rare tumors (paragangliomas and pheochromocytomas)
When evaluating a family history, certain patterns can be indicative of specific hereditary cancer syndromes. Breast and ovarian cancers tend to group together, and are often associated with the hereditary breast and ovarian cancer syndrome (HBOC).
Hereditary Cancer Syndromes
While the most common cause of hereditary breast and ovarian cancer syndrome are mutations in BRCA1 or BRCA2 genes, approximately 20 additional genes can be associated with increased risk for these cancer types. Many of the earliest studies of hereditary breast cancer risk focused on individuals of Ashkenazi Jewish ancestry. It is now known that individuals of Ashkenazi Jewish ancestry may harbor founder mutations in the BRCA genes, which are mutations that occurred in the original ancestors of this specific ethnicity. As such, individuals of Ashkenazi Jewish ancestry have a much higher chance of having mutations in the BRCA genes - 1/40 compared to the general population risk of 1/400. For someone with HBOC, their risk of developing breast cancer can be as high as 60-80%, and the risk of developing ovarian cancer 40-60%. Other cancer risks can also be associated with this syndrome, such as prostate cancer, pancreatic cancer, and melanoma.
Another common hereditary cancer syndrome is marked by a family history of colon and uterine/endometrial cancer. Lynch Syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC) can increase the lifetime risk for colon cancer to 60%, endometrial cancer to 60% and increase risk for a variety of other cancers such as ovarian, renal pelvis, bladder, gastric, pancreatic and even brain cancer. Five genes (MLH1, MSH2, MSH6, PMS2, EPCAM) can harbor a germline mutation which causes Lynch Syndrome, and each gene confers a different set of risks for these cancer types.
Additionally, more rare cancer types can be strongly associated with hereditary cancer syndromes. Specifically, cancer diagnoses of diffuse gastric cancer, paragangliomas, pheochromocytomas, hemangiomas, medullary or follicular thyroid cancer, renal cell carcinoma in young people, and adrenocortical carcinomas are all cancers that could be a sign of a hereditary cancer syndrome.
Both HBOC and Lynch Syndrome are caused by an inherited mutation in one out of two copies of these genes. If parents each carry a mutation in the same gene, and the child inherits both non-working copies of this gene (25% chance), the child will have an increased risk of pediatric cancer. For this reason, individuals who have tested positive for mutations in genes related to HBOC or Lynch Syndrome and are considering family planning should have their partner tested regardless of their partner’s family history.
Genetic Testing
Recognizing specific signs and patterns in a family history should prompt providers to refer patients to genetic counselors. Genetic counselors spend time taking an extended medical and family history in order to provide an accurate risk assessment. Not all family history confers the same level of risk, and specific genetic testing options will be based on the family history, and whether the patient meets the National Comprehensive Cancer Network’s (NCCN) guidelines for genetic testing. During the session the genetic counselor will explain the process of genetic testing, including details of what information is examined, possible results, and implications of those results for the patient and the family. The process of genetic testing varies depending on the clinical laboratory, but standard testing for hereditary cancer syndromes takes 3-4 weeks, with many patients who meet NCCN criteria having an out-of-pocket cost of $100 or less.
Genetic testing for hereditary cancer predisposition syndromes often occurs in the format of panel testing, where multiple genes associated with cancer risk are analyzed at once. Panel testing can be cancer specific such as a breast and gynecological cancers panel or a panel only including genes associated with paragangliomas and/or pheochromocytomas. Larger, multi-cancer panels are also available and these are ordered the most often, but it is the patient’s choice. For example, if the only reason someone meets genetic testing criteria is due to a first degree relative (sibling, parent, child) having pancreatic cancer and they are only concerned about the pancreatic cancer in their family, a pancreatic cancer panel can be ordered for them. Currently, if someone tests positive for a pancreatic cancer gene, they may be eligible for pancreatic cancer screening at an academic medical center starting at age 50. The current screening consists of contrast-enhanced MRI/magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound (EUS) for such high- risk individuals. Screening methodologies are usually alternated each year, but there is no current standardization.
Typically, genetic counseling is only provided to individuals 18 years of age and older. Mutations in the majority of these genes increases the risk for adult-onset cancers, and as such testing is usually deferred until the age of 18 to allow the patient to make an autonomous decision about testing. In rare cases, germline mutations increase risk for childhood onset cancers, and in this scenario, testing is facilitated by a specialized pediatric team.
The goal of genetic testing is to identify mutations in an individual or family in order to implement recommended screening measures. NCCN provides screening and surveillance guidelines for individuals who are at high risk of developing cancer due to a genetic predisposition. These recommendations have data that suggests that they reduce morbidity and mortality associated with an inherited cancer predisposition syndrome. As research around early cancer detection progresses rapidly, these guidelines and recommendations are continuously updated. As such, it is recommended that NCCN guidelines be assessed via their website for the most up to date recommendations.
Screening for Cancer
Screening recommendations are based on the cancer type and the level of risk that a mutation in a specific gene confers, and so not everyone with a diagnosis of HBOC will have the same screening guidelines. An example of how a hereditary cancer syndrome can impact screening is with the BRCA genes. In the general population, it is recommended that women begin annual mammograms at age 40 to address breast cancer risk. For BRCA female mutation carriers, breast cancer screening should begin at age 25 with annual breast MRIs with intravenous contrast. Beginning at age 30, BRCA mutation carriers will be advised to begin annual mammograms in addition to their annual breast MRI. Prophylactic surgical options, such as risk reducing bilateral mastectomy, are also discussed with BRCA female mutation carriers as an alternative to increased screening. Preventive endocrine therapy can also be considered.
Female BRCA mutation carriers are also at increased risk for ovarian cancer. Unlike breast cancer screening, there is no proven effective screening method for ovarian cancer. Transvaginal ultrasounds and CA-125 blood tests can be offered, but they have no proven efficacy in detecting ovarian cancer at early stages. Therefore, for women who test positive for a germline BRCA mutation, the recommendation is removal of the ovaries between the ages of 35 and age 40. NCCN currently states that it is reasonable to delay this risk-reducing salpingo-oophorectomy surgery in BRCA2 carriers until ages 40-45 unless someone in the family was diagnosed with ovarian cancer at an earlier age.
Both men and women BRCA carriers are at increased risk for pancreatic cancer as well as melanoma. Screening for BRCA carriers for pancreatic cancer is dependent on family history, and melanoma screening is the same as the recommended annual full body skin exam for the general population. Male BRCA carriers are at increased risk for prostate cancer and are recommended to begin prostate cancer screening via annual PSA at age 40. Male breast cancer screening recommendations vary, but minimum recommendations consist of an annual clinical breast exam for male BRCA carriers beginning at age 35.
Screening and surveillance recommendations can change even if someone has a negative genetic testing result. Additional contributing factors, such as family history, personal history and risk models are all evaluated when the genetic counselor discloses results and provides a final risk assessment for the patient. For example, any individual with a first degree relative with breast cancer is considered to have double the lifetime risk to develop breast cancer. This is due to assumed shared environmental factors, lifestyle factors, and additional genetic factors that we are not able to test for given current technology and understanding. As such, many patients who test negative on genetic testing will still meet a threshold for increased cancer screening and will be referred to additional providers to discuss specific recommendations.
Genetic Testing in the Affected Patient
When offering genetic testing to individuals, it is always most informative to test the person in the family who has been affected with the most relevant cancer at the youngest age. If a family history consists of three female breast cancers - one at age 86, one at age 65, and one at age 38, the individual with the breast cancer at age 38 is most likely to have a genetically driven breast cancer, and therefore is most likely to test positive. If testing is offered to the 86-year-old and she is negative, it still does not inform us about the other individuals in the family, and perhaps there could be a genetic mutation responsible for the younger ages of cancer diagnosis.
Genetic Information Non-Discrimination Act
If an unaffected individual is being offered testing, it is important to review the specifics of the law protecting them against genetic discrimination. The Genetic Information Non- Discrimination Act (GINA) was passed in 2008 as a part of the Affordable Care Act. GINA restricts employers and other entities covered by Title II from requesting, requiring or purchasing genetic information, and strictly limits the disclosure of genetic information. This law prevents health insurers and employers from discriminating against someone based on his or her genetic information. However, the law does not include protection from discrimination by life, disability, and long-term care insurance companies.
Direct-to-Consumer Genetic Testing
Finally, it is important to note that not all genetic testing is created equal. While direct-to- consumer genetic testing is steadily increasing access to genetic testing for a variety of individuals, it is not considered a clinical level test. Direct-to-consumer genetic testing often assays only a small fraction of possible mutations, and so a negative test result is not considered a comprehensive, or clinical level negative result. A patient should never have their screenings determined by or be discharged from high-risk cancer screening based on a negative direct-to-consumer test result. Individuals with negative direct-to- consumer genetic testing with a strong family history of cancer should be referred to genetic counseling for a full risk assessment and additional clinical level testing that is considered comprehensive.
Conclusion
Genetics and Cancer - does family history matter? The answer is a resounding yes.
While family history is not the only factor in considering an individual’s risk for cancer, it
is often a major aspect of the many pieces genetic counselors and other genetic
professionals use to assess an individual's cancer risk. If the family history of a patient
seems unusual, that patient may benefit from a referral to a genetic counselor or
genetics provider for a full risk assessment. That initial assessment may start a chain
reaction and reduce the chances that patients and their family members will be
diagnosed in the future with a late-stage cancer.
Editor’s note: Male and female in this article refer to sex assigned at birth. Specific recommendations and stipulations for cancer screening may exist for individuals who do not identify as cis gender.
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References
1 https://www.cancer.gov/about-cancer/understanding/statistics. Accessed June 19, 2023. 2 Giaquinto AN, Sung H, Miller, KD, et al. Breast Cancer Statistics, 2022. CA: A Cancer Journal for Clinicians. 2022; 72(6). doi:10.3322/caac.21754 3 Kontomanolis EN, Koutras A, Syllaios A, et al. Basic Principles of molecular biology of cancer cell – Molecular cancer indicators. JBUON. 2021; 26(5): 1723-1734. https://www.jbuon.com/archive/26-5-1723.pdf Accessed June 19, 2023 4 Bertram JS. The molecular biology of cancer. Mol Aspects Med. 2000;21(6):167-223. doi:10.1016/s0098-2997(00)00007-8 5 National Cancer Institute. The Genetics of Cancer. https://www.cancer.gov/about- cancer/causes- prevention/genetics#:~:text=Inherited%20genetic%20mutations%20play%20a,individual s%20to%20developing%20certain%20cancers. Accessed June 19, 2023. 6 Knudson Jr AG. Mutation and Cancer: Statistical Study of Retinoblastoma. Proceedings of the National Academy of Sciences. 1971;68(4):820-823. doi: 10.1073/pnas.68.4.820.