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Study: What are the genetics underlying 12 different cancer types?

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This study is about:

Inherited gene mutations found in some patients with one of 12 different cancers.

Why is this study important?

Researchers believe that at least 3% of all cancer cases have a strong hereditary component. One example is mutations, which greatly increase the risk of breast cancer. Other gene mutations also increase cancer risk, but not to the same extent as . Understanding how often gene mutations that confer moderately higher cancer risk occur in patients is a priority, as these mutations can still be passed to sons and daughters, and may affect patients’ treatment decisions.  According to the study authors, “Such discovery of new cancer susceptibility genes…will be an important step towards generating an actionable catalogue for personalized treatment of cancer.”

Study findings: 

  1. The most commonly mutated genes that increase cancer risk are: , , , , and .
  2. The percentage of patients with gene mutations that increase cancer risk varies among cancers. For example, 19% of ovarian cancer patients in this study had an that increases cancer risk, compared to only 4% of acute myeloid leukemia patients.

What does this mean for me?

This study identifies and catalogues gene mutations that increase a person’s susceptibility to cancer. Ultimately, the goal is to understand which mutations are clinically relevant and how they increase cancer susceptibility, so that health care providers can determine their patients’ cancer risks and treatment plans. However, we have no national guidelines on how to care for patients with some of the newly discovered mutations, or for patients with mutations that have been studied less extensively than mutations or the mutated genes that cause .  This study is an important step in helping researchers get a complete understanding of the role that inherited mutations play in different cancers. But more work needs to be done to fully assess the clinical relevance of these findings. Patients with mutations in genes that do not have national guidelines outlining risk management options should work with their health care providers to determine appropriate treatments and screenings for themselves and their families.

Posted 3/1/16

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Lu C, Xie M, Wendl MC, et al. “Patterns and functional implications of rare germline variants across 12 cancer types.” Nature Communications. Published online first on December 22, 2015. 


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.


This article is relevant for:

People diagnosed with cancer

This article is also relevant for:


people with a genetic mutation linked to cancer risk

people with a family history of cancer

people newly diagnosed with cancer

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Study background:

Some inherited gene mutations confer an extremely high risk of cancer, while others moderately increase cancer risk. In families with mutations in genes that moderately increase cancer risk, determining that cancer is hereditary may be more difficult. However, improved and more affordable genetic sequencing is helping researchers to learn more about these types of mutations.

In December 2015, Li Ding and colleagues from the Washington University School of Medicine in St. Louis and other institutions published in Nature Communications their study of gene mutations in cancer patients with one of 12 different types of cancer. Rather than sequencing a handful of genes known to be involved in cancer risk, the researchers used data from “exome sequencing,” which looks at the sequence of all genes used in the cell. Researchers then analyzed the data to find which mutations were inherited and known to be involved in cancer risk. This provides a more comprehensive catalog of the types of inherited gene mutations found in patients with these 12 types of cancer.

Researchers of this study wanted to know:

How genetics contributes to cancer development.

Population(s) looked at in the study:

The study looked at the sequences from 4,034 patients: about 88% of the patients were Caucasian, about 6% were African American, about 5% were Asian, and .4% were American Indian/Alaska Native. On average, patients were diagnosed at about 60 years old with one of the following 12 types of cancer:

  • Breast cancer
  • Glioblastoma, a type of brain cancer
  • Low grade glioma, a type of brain cancer
  • Head and neck cancer
  • Kidney renal clear cell carcinoma
  • Acute myeloid leukemia, a type of blood cancer
  • Two different types of non-small cell lung cancer
  • Ovarian cancer
  • cancer
  • Stomach cancer
  • Uterine cancer

Study findings: 

  1. Among the 12 cancers in this study, , , , , and genes were most associated with cancer predisposition.
    • The most commonly detected inherited gene mutations in breast cancer patients were in , , FANCM, and .
    • The most commonly detected inherited gene mutations in ovarian cancer patients were in , , PIK3C2G, , CNKSR1, , , and .
  2. Mutations in and were significantly associated with ovarian cancer.
  3. The percentage of patients with risk-increasing gene mutations varies among cancers. 
    • 19% of ovarian cancer patients in this study had an in a gene that increases cancer risk, compared to only 4% of acute myeloid leukemia patients, indicating that inherited mutations play a greater role in ovarian cancer than acute myeloid leukemia.
    • 11% of stomach cancer patients in this study carried an .


Researchers did not have information on the family histories of the cancer patients in this study, which would have provided more insight regarding the cancer risk conferred by the patients’ mutations. While the study looked at a sizeable group of patients, only a small number of them had some of the individual cancers. For example, only 178 cancer patients were identified, compared to 770 breast cancer patients, which makes it difficult to draw conclusions about cancer from the limited sample size.  Additionally, because the majority of the study population was Caucasian, the results are more relevant to that population, and not as relevant to individuals of other backgrounds.


It is important to remember that this single study does not prove that inherited mutations in some of these genes are directly associated with specific cancers.  According to the study authors, “This study is the largest to date that has integrated somatic and germline alterations to identify important genes across 12 major types contributing to cancer susceptibility, and our results provide a promising list of candidate genes for definitive association and functional analysis.” This means that the researchers found many new genes to study, but more work needs to be done before their data becomes clinically relevant. People with mutations in one of the genes highlighted in this study should talk to their health care providers about their cancer risk and how to manage it.

Posted 03/01/16

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network has guidelines on who should undergo genetic counseling and testing. If you have been diagnosed with breast cancer, you should speak with a genetics expert about genetic testing if any of the following apply to you:     

  • You have a blood relative who has tested positive for an  
  • You have any of the following:  
    • Breast cancer at age 50 or younger  
    • Male breast cancer at any age
    • Ovarian cancer at any age  
    • at any age 
    • Two separate breast cancer diagnoses
    • Eastern European Jewish ancestry and breast cancer at any age 
    • Lobular breast cancer and a family history of diffuse gastric cancer
    • For treatment decisions for people with breast cancer or people with early , breast cancer who are at high-risk for recurrence 
    • Testing of your tumor shows a mutation in a gene that is associated with


  • You have one or more close family members who have had:  
    • Young-onset or rare cancers 
    • Breast cancer at age 50 or younger
    • Male breast cancer, ovarian cancer, pancreatic cancer, or   cancer at any age
    • Two separate cancer diagnoses 
    • prostate cancer or  cancer that is high-risk or very-high-risk group. 

The American Society of Breast Cancer Surgeons (ASBrS) released guidelines in 2019 that recommend all women diagnosed with breast cancer have access to genetic testing for inherited mutations in breast cancer genes. 

If you are uncertain whether you meet the guidelines above and you are interested in or considering genetic testing, you should speak with a cancer genetics expert

Updated: 07/28/2023

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic counseling and testing for anyone diagnosed at any age with epithelial ovarian, or primary peritoneal cancer.

Updated: 11/13/2023

Expert Guidelines
Expert 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

Expert Guidelines
Expert Guidelines

The National Comprehensive Cancer Network (NCCN) has guidelines for genetic counseling and testing for people diagnosed with colorectal or endometrial cancer. People who have any of the following should speak with a genetics expert about genetic testing:

  • A tumor test result that suggests an (for example, an MSI-H or tumor). 
  • A blood relative who tested positive for an  linked to cancer.
  • Colorectal or endometrial cancer diagnosed before age 50.
  • Diagnoses of more than one cancer.
  • A family history of one or more first- or second-degree relatives with any of the following types of cancer diagnosed before age 50 or two or more first- or second-degree relatives with any of the following cancers diagnosed at any age:
    • colorectal
    • endometrial
    • ovarian
    • gastric
    • small bowel
    • biliary tract
    • pancreatic
    • urothelial
    • brain (usually glioblastoma)
  • Colorectal cancer and a personal history of polyps:
    • 10 or more adenomatous
    • 2 or more hamartomatous
    • 5 or more serrated close to the rectum

Updated: 11/12/2023

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • I carry a mutation in (, , , , , or ) What does this mean for me and my family?
  • I have an extensive family history of breast cancer, but my family does not carry a mutation. Should I consider genetic testing that looks for mutations in other genes?
  • I had breast cancer before age 50 but tested negative for a mutation in . Should I consider genetic testing that looks for mutations in other genes?

Open Clinical Trials
Open Clinical Trials

The following clinical trials include genetic counseling and testing. 

Other genetic counseling or testing studies may be found here.


Updated: 02/29/2024

Peer Support
Peer Support

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

Updated: 08/06/2022

Find Experts
Find Experts

The following resources can help you locate a genetics expert near you or via telehealth.

Finding genetics experts

  • The National Society of Genetic Counselors website has a search tool for finding a genetic counselor by specialty and location or via telehealth. 
  • 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. 
  • Gene-Screen is a third-party genetic counseling group that can help educate, support and order testing for patients and their families. 
  • JScreen is a national program from 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. 

Related experts

Genetics clinics

Other ways to find experts

Updated: 07/21/2023

Who covered this study?

New York Post

Scientists say cancer susceptibility is genetic This article rates 3.5 out of 5 stars

Oncotherapy Network

Investigators identify patterns of rare germline variants in 12 cancer types This article rates 3.5 out of 5 stars

Medical News Today

Study reveals how hereditary gene mutations affect risk of certain cancers This article rates 3.5 out of 5 stars

How we rated the media

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