Study: Rare mutations in PALB2, CHEK2, and ATM: how much do they increase cancer risk?

IN DEPTH REVIEW OF RESEARCH

Study background:

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.

Researchers of this study wanted to know:

What are the breast, ovarian, and prostate cancer risks associated with rare mutations in PALB2, CHEK2, and ATM?

Population(s) looked at in the study:

The participants in this study were from studies participating in three consortiums:

• The Breast Cancer Association Consortium (BCAC)
  • The majority of women in the studies from this consortium were of European ancestry (42,671 cases and 42,164 controls), compared to Asians (5,795 cases and 6,624 controls), and African Americans (1,046 cases and 932 controls). All of the women had invasive breast cancer.
• The Prostate Cancer Association Group to Investigate Cancer Alterations in the Genome (PRACTICAL)
  • The majority of men in the studies from this consortium were of European ancestry (22,301 cases and 22,320 controls), compared to African American men (623 cases and 569 controls).
• The Ovarian Cancer Association Consortium (OCAC)
  • The majority of women in the studies from this consortium were of European ancestry (16,287 cases and 14,542 controls), compared to Asian women (720 cases and 93 controls), and African American women (150 cases and 36 controls).

These consortiums are all part of the Collaborative Oncological Gene-environment Study (COGS) with a total of 176,873 participants.

Study findings: 

1. PALB2 mutations: There were three rare PALB2 mutations studied.
   • Two mutations were associated with increased breast cancer risk (PALB2 c.1592delT and PALB2 c.3113G>A),  while one was not (PALB2 c.2816T>G).  In all, 41 people were found to have the PALB2 c.1592delT mutation, 52 people had the PALB2 c.3113G>A mutation, and 295 people had the PALB2 c.2816T>G mutation.
   • None of the three rare PALB2 mutations studied showed an association with increased prostate or ovarian cancer risk.
2. ATM mutations:
   • The one rare ATM mutation (ATM c.7271T>G) studied was found to be associated with an increased risk of breast cancer, but not for prostate or ovarian cancer; only 13 people in this study had this mutation.
3. CHEK2 mutations: There were six rare CHEK2 mutations studied.
   • Four mutations  (CHEK2 c.349A>G, CHEK2 c.538C>T, CHEK2 c.715G>A, CHEK2 c.1036C>T) were associated with increased breast cancer risk, although the risk was not as high as the PALB2 and ATM mutations studied. The study showed that 62 people had the CHEK2 c.349A>G mutation, 300 people had the CHEK2 c.538C>T mutation, 24 people had the CHEK2 c.715G>A, and 11 people had the CHEK2 c.1036C>T mutation.
   • One mutation (CHEK2 c1312G>T) was not associated with increased breast cancer risk for European women, but was associated with increased prostate cancer risk for European men; 34 people in this study had this mutation.
   • One mutation (CHEK2 c.1343T>G) was only found in African men and women, and was associated with increased breast cancer and prostate cancer risk; 46 people in this study had this mutation.
   • None of the six mutations were associated with an increased risk for ovarian cancer.           

Limitations:

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

Conclusions:

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.

Posted 9/27/16

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