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Other mutations: People with very rare mutations in PALB2, CHEK2, and ATM
As multi-gene panel tests become more common, people are discovering they have mutations in genes that are not understood as well as BRCA. This can make it difficult to give patients accurate assessments of their cancer risk. For example, mutations in PALB2, CHEK2, and ATM are rare, but some specific changes in these genes are even less common. How can researchers study the cancer risks for people who carry rare mutations in these genes? This study's an international collaboration aiming to better understand the cancer risks of some PALB2, CHEK2, and ATM mutationsshows how difficult it can be to obtain enough data to provide accurate risk information. The findings are relevant only to the specific mutations in this paper and do not apply to all people with mutations in PALB2, CHEK2, or ATM. (9/27/16)
The breast, ovarian, and prostate cancer risks associated with rare mutations in PALB2, CHEK2, and ATM.
Some mutations in PALB2, CHEK2, and ATM are rare, making it difficult to determine the exact increased cancer risk for people who carry them. Patients with these mutations need to know this information so that they and their healthcare providers can make appropriate decisions about their cancer screenings and treatment.
It is important to remember that this study looked at just a handful of rare mutations in ATM, CHEK2 and PALB2, and cannot be used to draw conclusions about all mutations in these genes. However, this work indicates that it is important to know the exact mutation a patient has, as well as his/her personal and family history of cancer when developing a plan for cancer screening or assessing potential treatment options. More work needs to be done to confirm some of these findings, and to determine other rare mutations that may increase a patient’s cancer risk or not have an effect on a patient’s cancer risk. Patients should work with their healthcare providers to understand their genetic test results and determine what screenings and treatments are best for them.
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Many multi-gene panel tests look for mutations in PALB2, CHEK2, and ATM. However, while mutations in these genes are rare, some versions of the mutations are even less common. Our current understanding of cancer risk associated with mutations in PALB2, CHEK2, and ATM results from studying the most common mutations in these genes. From this past work, researchers realized that in some cases, mutations in PALB2 could increase cancer risk as much as a mutation in a BRCA gene, while mutations in CHEK2 and ATM increase cancer risk to a lesser extent but above the level of an average person.
Studying rare mutations is difficult because the study has to be large enough to see how mutations in these genes affect cancer risk. Yet researchers have a hard time finding enough people with these rare mutations to study cancer risk and draw conclusions that can be used to make cancer risk management decisions.
Melissa Southey and her colleagues from The University of Melbourne and other institutions around the world published work in the Journal of Medical Genetics in June 2016 that assessed the cancer risk associated with a handful of specific, very rare mutations in PALB2, CHEK2, and ATM.
What are the breast, ovarian, and prostate cancer risks associated with rare mutations in PALB2, CHEK2, and ATM?
The participants in this study were from studies participating in three consortiums:
These consortiums are all part of the Collaborative Oncological Gene-environment Study (COGS) with a total of 176,873 participants.
The cancer risks calculated in this study apply to very few people because, of the hundreds of mutations that can occur in PALB2, CHEK2, and ATM, the study looked at only 10 specific mutations. Because these are rare mutations, the sample size for some of them was too small, even from an international collaboration, to yield a definitive conclusion (especially as seen in the mutations that were carried by less than 20 people). Additionally, the international approach does not greatly improve the risk estimates for the mutations that are only found in certain populations (such as the CHEK2 mutation that was only found in African American patients). This means that the cancer risks calculated in this study might not apply to the few people who have one of these rare mutations. Finally, it is always important to remember mutation status is not the only measure of increased cancer risk. Even if a person has a mutation that was found to not increase cancer risk in this study, there are other factors that are involved in determining cancer risk including family history and lifestyle factors
The results of this study suggest that some of the rare mutations in PALB2 and ATM may be associated with increased risk of breast cancer, putting these women at “high risk.” This indicates that these women should have more screening and should discuss risk-reducing measures with their health care providers. However, more work needs to be done, especially in developing more methods that can be used to estimate these risks accurately for these rare mutations that are difficult to study with human populations. This study is a clear example of how much work and how many research participants are needed to get reliable estimates of cancer risks associated with specific mutations.
It is important to note that this study looked at a handful of specific mutations in PALB2, CHEK2, or ATM; it did not look at the risk of having any mutation in these genes. People with mutations in PALB2, CHEK2, or ATM should consult with a genetics expert who can look at both their gene mutation as well as their personal and family history of cancer to help them estimate their cancer risk.
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Southey MC, Goldgar DE, Winqvist R, et al. “PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS.” Journal of Medical Genetics. 2016; 0: 1-12. http://jmg.bmj.com/content/early/2016/09/02/jmedgenet-2016-103839.short?rss=1
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