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Study: Genes linked to aggressive prostate cancer

Summary

Previous research has linked some inherited mutations to prostate cancer risk. This study found a link to additional genes that should be added to prostate cancer gene panel tests. The study also looked at which genes were most closely linked to aggressive prostate cancer that is more likely to spread. (Posted 2/1/24)

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Genes linked to aggressive prostate cancer
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RELEVANCE

Most relevant for: People diagnosed with advanced prostate cancer.
It may also be relevant for:

  • people with a genetic mutation linked to cancer risk
  • people with a family history of cancer
  • people with prostate cancer

Relevance: Medium-High

Strength of Science: Medium-High

Research Timeline: Post Approval

Relevance Rating Details

What is this study about?

Experts have found that inherited mutations in several different genes can increase the risk of cancer. This study looked beyond the currently known cancer genes to see whether additional genes are linked to cancer. The study also looked at which genes were most closely linked to aggressive cancer that is more likely to spread.

Why is this study important?

Guidelines recommend genetic testing for anyone diagnosed with prostate cancer or cancer that has a grade of high-risk or very high risk. Results of genetic testing are used to guide screening and treatment and can also be used to help family members understand their cancer risk.

Currently, a few genes are known to increase the risk of cancer.  These genes (, , , and ) are included on cancer gene panels. This study found other genes that increase the risk of cancer.  The researchers suggest that these genes should be added to current cancer gene panels.

cancer tumors can be different from one another. In some cases the tumors are slow growing and in other cases they can be more aggressive requiring more intense treatment. Mutations in and possibly other genes have been linked to more aggressive cancers that are more likely to spread beyond the . cancers that spread can be life-threatening and require more aggressive treatment. Researchers wanted to learn if other gene mutations are likely to cause more aggressive cancer. This information can be used to help guide treatment decisions. 

Study findings

Study Population

The study included over 17,000 men of European ancestry with cancer. Just over half had aggressive cancer, and a little less than half had nonaggressive cancer. About a quarter of individuals with aggressive cancer had prostate cancer ( cancer that spreads beyond the into nearby tissues).

Results by gene mutation and cancer type

Gene People with mutation People with a mutation who had non-aggressive cancer People with a mutation who had aggressive cancer People with a mutation who had prostate cancer
277 (1.3%) 55 (0.7%) 222 (2.4%) 72 (3.0%)
202 (1%) 60 (0.7%) 142 (1.6%) 45 (1.9%)
42 (0.2%) 13 (0.2%) 29 (0.3%) 13 (0.5%)
27 (0.1%) 7 (0.1%) 20 (0.2%) 4 (0.2%)
XRCC2  10 (0.1%) 2 (0.0%) 8 (0.1%) 2 (0.1%)
MRE11A 23 (0.1%) 11 (0.1%) 12 (0.1%) 6 (0.3%)

  • 277 (1.3%) had a mutation. Of these, 222 (2.4%) had aggressive cancer; 72 people in this group (3.0%) had prostate cancer.  Overall, 55 (less than 1%) had nonaggressive cancer.

  • 202 (1%) had an mutation. Of these, 142 (1.5%) had aggressive cancer; 45 people in this group (2.0%) had prostate cancer. Overall, 60 (less than 1%) had nonaggressive cancer.  

  • 42 (0.2%) had an mutation. Of these, 29 (0.3%) had aggressive cancer; 13 people in this group (0.5%) had prostate cancer. Overall, 13 (0.1%) had non-aggressive cancer.  While a link between and aggressive cancer was not statistically significant in this study, the link between and prostate cancer was significant.

and XRCC2

  • This study found some evidence that inherited mutations in and XRCC2 were linked to aggressive cancer, although this link was not as strong as the links with , and .

MRE11

  • This study also found that inherited mutations in MRE11A were linked to prostate cancer, although this link was not as strong as the links with , and .

, , , GEN1 and SLX4

  • This study found that inherited mutations in , , , GEN1 and SLX4 may also be linked to aggressive cancer, although more research is needed to confirm this.

Other genes: POLK, POLH and MSH5

  • Inherited mutations in POLK, POLH and MSH5 are very rare. However, this study found that POLK and POLH were linked to aggressive cancer, while inherited mutations in MSH5 were linked to prostate cancer.  More research is needed to verify that these links exist.

Genes not linked to aggressive cancer

, , and have been linked to increased risk of cancer. However, in this study, these genes were not linked to aggressive cancer. For example, 318 participants (1.8%) had a mutation. Of these, 173 (1.0%) had nonaggressive cancer, compared to 145 (0.8%) who had aggressive cancer.

What does this mean for me?

If you have been diagnosed with cancer, genetic testing for an can help you make treatment decisions. Knowing if you have an can help you and your healthcare team make treatment decisions.  It can also help your relatives understand about their risks for cancer. 

Current cancer gene panels include , , , and . This study suggests that additional genes should also be included. Adding these genes can benefit those diagnosed with aggressive disease.  It may also benefit those diagnosed with cancer at any , as people with an are at risk of developing advanced disease.   

Reference

Darst B, Saunders, E, Dadaev, T, et al., Germline sequencing analysis to inform clinical gene panel testing for aggressive cancer. JAMA Oncology; 2023; Published online September 21, 2023.

Wyatt, A. Rare genetic drivers of lethal cancer. JAMA Oncology; 2023; Published online September 21, 2023.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 2/1/24

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • Should I have genetic testing with a cancer gene panel?
  • If testing is recommended, what genes are included with the test?
  • Should I be tested for any other cancer genes that are not included on the recommended cancer gene panel?
  •  How will genetic test results impact my care and treatment?

Guidelines
Guidelines

The National Comprehensive Cancer Network guidelines recommend genetic counseling and testing for the following people with  cancer who have:

  • a tumor test result that suggests an inherited mutation
    • for example, a tumor with a ,  or  mutation may indicate an in one of those genes 
  • a blood relative who tested positive for an  in a gene linked to  cancer
  •   cancer diagnosed at any age
  • cancer that has spread to the
  • localized cancer (hasn’t spread beyond the ) that is considered very high-risk or high-risk
  • intermediate-risk cancer with intraductal or cribriform features listed on the
  • a diagnosis of male breast cancer
  • Eastern European (Ashkenazi) Jewish ancestry
  • one or more relatives with:
    • breast, colorectal or endometrial cancer diagnosed at age 50 or younger
    • male breast cancer, triple negative breast cancer, ovarian cancer or pancreatic cancer at any age
    • , regional, very-high-risk, or high-risk cancer at any age
  • one or more close relatives with cancer diagnosed at age 60 or younger
  • three or more relatives on the same side of the family with biliary tract, breast, colorectal, endometrial, glioblastoma, or other cancers

Speak with a genetic counselor if you have questions about whether you meet guidelines for genetic testing. 

Updated: 02/01/2024

Related resources
Related resources

The following resources focus on  cancer. 

Updated: 08/06/2022

Peer support
Peer support

The following organizations offer peer support services for people with or at high risk for cancer:

Updated: 03/08/2023

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Article Rating Details

Study Rating Details

Relevance: Medium-high

  • The research adds to our understanding of the genes that are associated with aggressive prostate cancer. 
  • This study only included people of European ancestry. It is not clear whether the findings of this study are generalizable to people of other ancestries.
  • The study has clinical utility.  It suggests that other genes should be added to prostate cancer gene panel tests. 

Scientific Strength: Medium

Strengths:

  • The large number of people included in the study provides insight into the genes that increase the risk of aggressive prostate cancer in the European population.

Limitations:

  • Almost half of participants with nonaggressive prostate cancer had 10 or more years of follow-up.  For these participants, it could be confirmed that they were alive and did not have cancer that returned.  However, some nonaggressive cases may have been misclassified, which could impact the interpretation of the results.
  • Study participants were limited to those of European ancestry.  These results may not be generalizable across populations.

Research Timeline:  Post-approval

  • Prostate cancer gene panel tests are already used in the care of people with prostate cancer. However, the study results raise questions about the addition of other genes to current prostate cancer gene panels.