Box 1 Basic Elements Of Genetics Care Delivery And Germline Testing
Aspects of germline genetic testing
Testing DNA from non-cancerous cells to detect variation associated with potential risk of disease or effect on treatment.
Disease risk is predominantly determined by the effect that the variant has on the ability of the gene to translate into a functioning protein.
The goal of germline genetic testing in oncology is to assess an individuals cancer predisposition and understand why a specific cancer developed based on pathogenic variants in genes implicated in important cellular processes.
Germline testing can also be conducted in oncology to inform targeted therapy options, particularly in the metastatic setting.
Variants detected in germline testing can be passed down or inherited by offspring. Germline testing differs from somatic genetic testing of a tumour assessing for somatic variants, which are usually acquired in tumour formation. Confirmatory germline testing of somatic variants might be indicated to determine hereditary nature.
Aspects of genetic counselling
Evaluating a patients medical and family history to assess the likelihood of a genetic predisposition and advise appropriate genetic testing.
Providing education regarding genetic testing, inherited health risk, or effect on treatment.
Supporting patients in making genetic testing decisions.
Interpreting genetic testing results and helping patients to understand and adjust to potential medical, familial and psychosocial implications.
Clinical scope of a genetic counsellor
Risk Of Other Cancers In Multiple
Several reports have suggested an elevated risk of various other cancers among relatives within multiple-case prostate cancer families, but none of these associations have been established definitively.
In a population-based Finnish study of 202 multiple-case prostate cancer families, no excess risk of all cancers combined was detected in 5,523 family members. Female family members had a marginal excess of gastric cancer . No difference in familial cancer risk was observed when families affected by clinically aggressive prostate cancers were compared with those having nonaggressive prostate cancer. These data suggest that familial prostate cancer is a cancer sitespecific disorder.
A study from the Swedish Family Cancer Database reported an increased risk of the following cancers in families where multiple members had a prostate cancer diagnosis: myeloma , kidney cancer , nonthyroid endocrine tumors , melanoma , nervous system tumors , and female breast cancer . It remains to be determined whether these associations are from a common genetic basis, shared environment, or a combination of factors.
Men With Metastatic Prostate Cancer Need Genetic Testing
Nearly 165,000 men in the US developed prostate cancer in 2018, and about 29,500 of these men will most likely die of it. Black men are at a higher risk, as are men with a family history of prostate cancer, particularly if a father, brother, or multiple male family members had the disease. Until recently, Prostate exams and PSA tests have been the only screening tools for prostate cancer in men.Elias Obeid, MD, MPH
Genetic testing was not done for men because we lacked data on who to test and what to test for, said Elias Obeid, MD, MPH, a clinical cancer geneticist at Fox Chase Cancer Center. We now know that there is a higher incidence of prostate cancer in men with certain mutations of the DNA repair genes, including BRCA1, BRCA2, ATM, PALB2, and FANCA.
In the past few years, specific germline mutations have been identified in a high frequency in men with metastatic prostate cancer. In one study, a significant proportion of patients with such mutations and castration-resistant metastatic prostate cancer responded to PARP inhibitor therapy. This suggests that genetic tests for defects in DNA-damage repair genes can identify individuals and families with a predisposition to prostate cancer, as well as stratify patients for targeted therapies using a PARP inhibitor or clinical trial eligibility.
The findings from those and other studies were compelling enough for NCCN guidelines to recommend genetic testing for all men with metastatic prostate cancer.
Who Should Get Genetic Counseling For Prostate Cancer
In general, there are three groups of men who should consider genetic counseling and testing for prostate cancer:
Results Could Lead To Earlier Cancer Screening
Finding out you have a genetic mutation linked to prostate cancer benefits the whole family. Other family members also may want to think about testing. This will tell them if they have inherited the same gene.
This is called “cascade testing” and is often offered to family members after a discussion with a genetic counselor. Men who are found to have a genetic mutation should start being screened for prostate cancer at a younger age than men without a family history of the disease.
The first step in screening is a prostate-specific antigen blood test. In general, the higher a man’s PSA level, the more likely he has prostate cancer. If prostate cancer is suspected, the doctor may suggest more tests. This could include a prostate biopsy . In a man with a genetic mutation, the doctor may use a lower PSA score to decide whether a biopsy is needed.
If you have an inherited risk of prostate cancer, your doctor may talk to you about certain lifestyle changes. These can include adding exercise, quitting smoking and keeping a healthy weight, which may lower your risk of cancer.
“Many men are surprised to hear inherited genes can play a major role in prostate cancer,” Dr. Morgan said. “But when I talk with men who may benefit from testing about why they should consider it, they often decide to get tested in order to receive more health information that can help them and their family make vital health decisions.”
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Polygenic Risk Score In Asians
While most large-scale GWASs recruited genotypic data from mainly Caucasian and European cohorts, a handful of attempts have been made to generate a PRS for Asian populations . A recent article utilizing a multi-ethnic cohort from the PRACTICAL Consortium reported results based on a PRS using 46 SNPs . Asian ancestry composed 3.0% of the entire the 80,491 dataset , and self-reported race/ethnicity revealed East and South Asians as 1.5% and 0.2% . Males of Asian genetic ancestry in the 98th percentile of the PRS had a hazard ratio of 3.77 and 4.14 for any PCa and aggressive PCa compared to the 30th to 70th percentile. This was comparable to performance in the European subgroup, in which the top 2% had a HR of 4.34 and 4.40 for any PCa and aggressive PCa, respectively. However, despite efforts to compare inter-ethnic variations in PRS performance, this study was limited by the grossly small number of non-European cohorts and limited analysis of local ancestry. Also, because the PRS was constructed largely based on European GWASs, SNPs significant in Asians may have been underrepresented.
Prostate Cancer Gene Expression Testing At Ucsf
A major challenge in tailoring prostate cancer care is identifying men who require immediate or aggressive treatment and those who possess prostate cancers that can safely be surveyed. Several prediction tools have been developed and tested at UCSF including the CAPRA, and CAPRA-S scores. Recently, several commercially available genetic tests taken from an individuals prostate cancer tissue have become available that may assist urologists and patients in clinical decision making. UCSF Department of Urology has collaborated with Genomic Health, Inc and Myriad Genetics to evaluate genomic biomarkers, as well as conducted several independent studies of these markers.
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Potential Risks Of Genetic Testing
While genetic testing for cancer has several benefits, there are also some risks associated with it as well. These can include:
- Psychological impact. Receiving a result thats positive or inconclusive, as well as deciding whether to share your result with family members, may lead to high levels of stress or anxiety.
- Guilt. Its possible that you may feel guilt after receiving a negative result for a variant thats present in other members of your family.
- Cost. Genetic testing can be expensive and may not be covered by some health insurance plans.
A healthcare professional may recommend genetic testing for cancer when:
- you have a family or personal history of a specific cancer
- testing can effectively determine the presence of gene variants that increase the risk of developing this cancer
- the results of the test can be used to help guide preventative measures or future treatments
Now lets look at some examples of situations where you may consider genetic testing for cancer.
Predictive Genetic Tests For Cancer Risk Genes
Cancer is not usually inherited, but some types mainly breast, ovarian, colorectal and prostate cancer can be strongly influenced by genes and can run in families.
We all carry certain genes that are normally protective against cancer. These genes correct any DNA damage that naturally happens when cells divide.
Inheriting faulty versions or “variants” of these genes significantly raises your risk of developing cancer, because the altered genes cannot repair the damaged cells, which can build up and form a tumour.
BRCA1 and BRCA2 are examples of genes that raise your cancer risk if they become altered. Having a variant BRCA gene greatly increases a woman’s chance of developing breast cancer and ovarian cancer. They also increase a man’s chance of developing male breast cancer and prostate cancer.
BRCA genes are not the only cancer risk genes. Researchers recently identified more than 100 new gene variants associated with an increased risk of breast, prostate and ovarian cancer. Individually, these new gene variants only slightly increase the risk of cancer, but a combination could mean a high risk overall.
If you or your partner have a high-risk cancer gene, such as an altered version of BRCA1, it can be passed on to any children you have.
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What Can Genetic Testing Tell Men About Prostate Cancer
Genetic counseling and testing can be powerful tools in understanding the risk you and your family members face for developing cancer, as well as how to potentially treat it.
Test results may influence your:
- Screening frequency: If you do not have prostate cancer but have a genetic mutation that increases your risk of developing it, your doctor may recommend more active surveillance from a younger age. This could include prostate-specific antigen testing or digital rectal exams .
- Diagnosis: Men who have prostate cancer caused by a genetic mutation may be more likely to develop an aggressive form of the disease. Knowing this might impact your initial treatment options.
- Treatment options: Men with specific genetic mutations may respond better to certain drugs and treatments. For example, men with metastatic prostate cancer who also have BRCA mutations may benefit from a targeted therapy known as a PARP inhibitor. Having certain genetic mutations also may affect eligibility for some clinical trials.
- Relatives’ health decisions: Genetic testing doesnt just affect you. It also can benefit family members by helping them understand and manage their risk for cancer. Depending on your results, other family members may want to get tested. If the same mutation is discovered, they can begin screening for the disease from an earlier age, if recommended.
Unique Aspects Of Genetic Counselling For Men With Prostate Cancer
With the expansion of genetic testing criteria for prostate cancer,, improved insight is needed in to how men process the pre-test counselling discussion, understand their genetic results and handle the anxiety or guilt of having an inherited genetic mutation. Many men might have high satisfaction with their genetic evaluation experience, but some men may have difficulty with the process. Patients might need additional resources or support to understand their genetic results. For example, results are emerging that report that some men who undergo prostate cancer genetic testing might have limited understanding of VUS. Given that ~30% of men undergoing prostate cancer germline testing will have VUS reported,, this proportion represents a substantial number of men in need of reinforcement of information to enhance understanding of results and to limit propagation of misinformation in families.
Overall, identifying and addressing the clinical, genetic and psychosocial issues for men is important for facilitating decision-making on genetic testing and for supporting men in their cancer treatment and genetic evaluation experience.
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My Family Member Has Prostate Cancer Should I Get Germline Testing
If one of your blood relatives has cancer and has tested positive for certain genetic traits, their doctor or genetic counselor may offer germline testing to other members of the family.
This is known as cascade testing. It can help you and other family members learn if you have an increased risk for developing certain types of cancer, including prostate cancer.
If you test positive for certain genetic traits that raise your risk for cancer, your doctor or genetic counselor may:
- advise you to begin cancer screenings at a younger age than usual
- encourage you to get more frequent cancer screenings than usual
- recommend lifestyle changes or other strategies to reduce your risk for developing cancer
Your doctor will likely advise you to get early cancer screenings if you have a close relative with prostate cancer, even if you havent gone through germline testing.
Prostate cancer screening may be conducted with a simple blood test, known as the prostate-specific antigen , as well as a digital rectal examination .
If you test positive for elevated levels of PSA, or you have abnormal exam results, your doctor may order a prostate biopsy or additional tests to check for cancer.
Some genes linked to prostate cancer are also linked to other cancers, such as breast and ovarian cancer. Talk to your doctor to learn which cancer screenings you should get and when you should get them.
Other Factors To Consider
Genetic testing has limitations and emotional implications. These may include:
Depression, anxiety, or guilt. A positive test result means a gene mutation exists. This result may bring difficult emotions. Some people may think of themselves as sick, even if they never develop cancer. Negative test results may also cause difficult emotions. For example, some people may experience guilt if they do not have a gene mutation that other family members have.
Family tension. People are generally encouraged to tell family members about test results because they can be important for the health of family members. But this information could also complicate family dynamics. Learn more about sharing genetic test results with your family.
A false sense of security. A negative result means a specific genetic mutation is not present. But people with negative results may still develop cancer. A negative result only means the persons risk is average. Each persons risk for cancer is also affected by other factors. For example, lifestyle, environmental exposure, and medical history.
High cost. Genetic testing can be expensive. It is particularly expensive if health insurance does not pay for it.
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Where To Access Genetic Testing For Prostate Cancer Risk
Genetic tests for prostate cancer risk may be available in the NHS for men with a high chance of prostate cancer due to a being at risk of a genetic mutation. If you would like to learn more ask your GP to refer you to the local NHS genetics clinic. You will usually be sent a family history questionnaire for assessment as a first step and then you may be invited for a genetic counselling appointment. The link below provides all the information about the NHS Genetic testing centres in the UK by region.
Identifying Genes And Inherited Variants Associated With Prostate Cancer Risk
In This Section
An advantage of this approach is that recent admixtures result in long stretches of linkage disequilibrium of one particular ancestry. As a result, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer, than the number of markers needed for successful GWAS.
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Management Of Prostate Cancer Based On Germline Mutations
Historically, germline testing for cancer predisposition syndromes was performed to inform cancer risk, screening and cancer risk-reduction measures. However, advances in precision medicine have heralded a new era of expanded therapeutic utility of germline testing, which is now highly relevant to prostate cancer,,,,,, . Hereditary cancer management for syndrome-associated cancers including and beyond prostate cancer is also crucial,.
Genetically based management of men with early-stage prostate cancer is also evolving regarding active surveillance discussions. In one study, 6 of 11 men with BRCA2 mutations on active surveillance had significant upgrading of biopsy samples, either scheduled or prompted by serum PSA levels, compared with 283 of 1,200 non-BRCA2 carriers . Surveillance biopsies were performed at 12 years after prostate cancer diagnosis based on the cohorts included in the analysis. These early results point to the potential need to include germline test results, particularly for BRCA2 mutations, in active surveillance discussions further data are needed for definitive recommendations and current practice is evolving based on expert consensus,.