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

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Contents

At a glance Questions for your doctor
Findings                In-depth                 
Clinical trials Limitations
Guidelines Resources


STUDY AT A GLANCE

This study is about:

The breast, ovarian, and cancer risks associated with rare mutations in , , and .

Why is this study important?

Some mutations in , , and 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.

Study findings: 

  1. mutations: There were three rare mutations studied.
    • Two were associated with an increased risk of breast cancer, and one was not.
    • None of the three rare mutations studied were associated with increased or ovarian cancer risk.
  2. mutations:
    • One rare mutation was associated with an increased risk of breast cancer, but not with or ovarian cancer.
  3. mutations: There were six rare mutations studied.
    • Four were associated with increased breast cancer risk, although the risk was not as high as those found in some of the and mutations. 
    • One mutation was not associated with increased breast cancer risk for European women, but was associated with increased cancer risk for European men.
    • One mutation that was only found in African men and women was associated with both increased breast cancer and cancer risk.
    • None of the six mutations were associated with an increased risk for ovarian cancer.     

What does this mean for me?

It is important to remember that this study looked at just a handful of rare mutations in , and , 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.

Posted 9/27/16

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References

Southey MC, Goldgar DE, Winqvist R, et al. “, and 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

This article is relevant for:

People who tested positive for one of the rare variants in CHEK2, ATM or PALB2 that are covered in this study

This article is also relevant for:

People with a genetic mutation linked to cancer risk

Previvors

Be part of XRAY:

Expert Guidelines Expert Guidelines

The National Comprehensive Cancer Network (NCCN) provides guidelines for management of breast cancer risk in people with inherited mutations linked to breast cancer. We recommend that you speak with a genetics expert who can look at your personal and family history of cancer and help you to determine the best risk management plan. 

 or

  • Beginning at age 40 (or earlier based on family history):
    • recommend annual  (consider 3D , if available).
    • consider annual breast  with contrast.

, or

  • No specific breast cancer screening guidelines. Risk management should be based on family history of cancer.

 

  • Beginning at age 30 (or earlier based on family history):
    • recommend annual  (consider 3D , if available).
    • consider annual breast  with contrast.
    • discuss risk reducing mastectomy. 

  • Beginning at age 30 (or earlier based on family history):
    • recommend annual  (consider 3D , if available).
    • recommend annual breast  with contrast.
    • discuss risk reducing mastectomy. 

  • Be aware of endometrial cancer symptoms.
  • Consider endometrial biopsy every 1-2 years beginning at age 35.
  • For post-menopausal women, consider transvaginal after discussion with your doctor. 
  • Consider risk-reducing hysterectomy. 

  • Clinical breast examination by a health care provider twice a year starting at age 30.
  • Recommend annual .
  • Recommend annual .

  • Breast self-awareness beginning at age 18.
  • Clinical breast examination by a health care provider twice a year starting by age 20.
  • Annual breast  with contrast beginning at age 20 (or  if  not available, but  is preferred) or at the age of earliest breast cancer diagnosis if there is a history of breast cancer before age 20 in family.
  • Annual breast  and  beginning at age 30 (consider 3D ). 
  • Consider risk reducing mastectomy.

Updated: 03/19/2022

Questions to Ask Questions to Ask Your Doctor

  • I was diagnosed with breast cancer before age of 45; should I consider genetic testing?
  • I tested negative for mutations in and , despite being diagnosed with breast cancer before the age of 45; should I consider additional genetic testing?
  • Members of my family have a mutation in , , or ATM; should I consider genetic testing?
  • I tested positive for a mutation in a gene for which cancer risk is not well understood; how can I be sure I get new information on my cancer risk as more research is completed?
  • Can you refer me to a genetics expert?

Open Clinical Trials Open Clinical Trials

The following are risk-management studies enrolling people with inherited mutations. Check study listings or contact the study team to see if you are eligible. 

Multiple cancers

cancer

  • NCT03805919: Men at High Genetic Risk for  Cancer. This is a  cancer screening study using  in high risk men. This study is open to men with , , , , , HOXB13, , , ,  and other inherited mutations.
  • NCT05129605: Cancer Genetic Risk Evaluation and Screening Study (PROGRESS).  This study will look at how well  MRI works as a screening tool for men at high risk for cancer. This study is open to men with inherited mutations in , , , , , , HOXB13, , , , , , , , , and other genes. 

Ovarian cancer

Pancreatic cancer

Additional risk-management clinical trials for people with inherited mutations may be found here.

Updated: 03/14/2022

Peer Support Peer Support

FORCE offers many peer support programs for people with inherited mutations. 

Updated: 03/12/2022

Find Experts Find Experts

Health care providers who are specially trained in genetics can help you more clearly understand your risk for . The following resources can help you locate a genetics expert in your area.

  • The National Society of Genetic Counselor website offers a searchable directory for finding a genetic counselor by state and specialty. To find a genetic counselor who specializes in cancer genetics, choose "cancer" under the options "Area of Practice/Specialization." 
  • InformedDNA is a network of board-certified genetic counselors providing this service by telephone. They can also help you find a qualified expert in your area for face-to-face genetic counseling if that is your preference. 
  • JScreen is a national program based out of Emory University that provides low-cost at-home genetic counseling and testing with financial assistance available.
  • Grey Genetics provides access to genetic counselors who offer genetic counseling by telephone. 
  • The Genetic Support Foundation offers genetic counseling with board-certified genetic counselors. 
  • FORCE's toll-free helpline at: 866-288-RISK, ext. 704 will connect you with a volunteer board-certified genetic counselor who can answer general questions about genetic testing and cancer and help you find a genetics expert near you. 
  • FORCE Peer Navigator Program will match you with a volunteer who has undergone genetic counseling and can help you navigate resources to find a genetic counselor near you.
  • Ask your doctor for a referral to a genetics expert. 

Updated: 03/16/2022

Who covered this study?

Breast Cancer News

Rare genetic mutations tied to higher risk of breast cancer This article rates 3.5 out of 5 stars

News.com.au

Also published in:

The same article was also covered by Nine.com.au

Rare genes increase breast cancer risk This article rates 2.5 out of 5 stars

Medical Xpress

World-first study confirms rare genetic mutations cause high breast cancer risk This article rates 2.5 out of 5 stars

How we rated the media

IN DEPTH REVIEW OF RESEARCH

Study background:

Many multi-gene panel tests look for mutations in , , and . 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 , , and results from studying the most common mutations in these genes. From this past work, researchers realized that in some cases, mutations in could increase cancer risk as much as a mutation in a gene, while mutations in and 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 , , and .

Researchers of this study wanted to know:

What are the breast, ovarian, and cancer risks associated with rare mutations in , , and ?

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

Share your thoughts on this XRAYS article by taking our brief survey.

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