Inherited Mutations Play Greater Role in CRC Than Previously Thought

Shannon Connelly
Published Online: Thursday, Apr 20, 2017

Matthew B. Yurgelun, MD

Matthew B. Yurgelun, MD

Nearly 10% of patients with colorectal cancer (CRC) had germline cancer susceptibility gene mutations, according to a study recently published in the Journal of Clinical Oncology. This is much greater than the 3% to 4% previously thought, said lead study author Matthew B. Yurgelun, MD.  

The study, which was conducted at the Dana-Farber Cancer Institute, included 1058 patients who were not preselected for age at diagnosis, personal/family history, tumor microsatellite instability (MSI), or mismatch repair (MMR) deficiency. Germline testing was conducted for 25 genes linked to inherited cancer risk.  

The results showed that 105 patients (9.9%; 95% CI, 8.2%-11.9%) had at least 1 pathogenic mutation, including 33 patients (3.1%) with Lynch syndrome (LS). Among 29 evaluable LS CRCs, all but 1 showed abnormal MSI/MMR results. Non-LS gene mutations were detected in 74 (7%) patients, including BRCA1/2 mutations in over 1% of patients.  

In an interview with OncLive, Yurgelun, assistant professor of Medicine, Harvard Medical School, and a researcher at the Dana-Farber Cancer Institute, discussed the study and its implications for patients with CRC and their families.

OncLive:  Please provide an overview of your study?

Yurgelun: We analyzed 1058 individuals who had a diagnosis of colon cancer who were seeking care at the Dana-Farber Cancer Institute. As a part of their clinical care here, they consented to have blood drawn for the purposes of research. For this study, we then went on to perform germline testing on all individuals using a commercially available 25-gene panel to look for inherited mutations in genes associated with inherited cancer risk. Some of the genes are linked to inherited CRC risk, and some genes are linked to inherited risk of other cancers, but not necessarily CRC.   

For a long time, we’ve known that inherited factors do play a large role in the ideology and risk of CRC, although historically we thought that that accounts for a pretty small fraction of individuals with colorectal cancer, probably around 3% to 4%.   

One of the key findings from our study here, however, was that inherited mutations in a cancer susceptibility gene were found in nearly 10% of individuals who we analyzed with this 25-gene panel. These individuals were not specifically selected for factors we traditionally associate with inherited risks of cancer. For example, these individuals were not specifically selected for being young at the time of their colon cancer diagnosis, they were not specifically selected based on factors in their tumor, or based on any sort of family history of cancer.   

The fraction of individuals found to have inherited mutations in cancer susceptibility genes was quite a bit higher than what we would have expected in the past.  

Was BRCA included in the gene panel?

BRCA1 and BRCA2 were analyzed as part of this 25-gene panel, and those are genes that historically have been known to confer particularly high lifetime risks for female breast cancer, ovarian cancer, and to a lesser extent, male breast cancer, pancreatic cancer, and prostate cancer, but have never really been linked to CRC risk.   

Within this study, as part of the 25-gene panel, individuals were tested for germline mutations in BRCA1 and BRCA2. We found that over 1% of these individuals, who again, were not specifically selected for any high-risk features, indeed did have inherited mutations in BRCA1 or BRCA2, which is quite a bit higher than what we would expect if we just did testing on random people selected from the general population.   

To us, this at least suggested that there may be a true link between mutations in these genes and CRC risk, but certainly more studies are needed to tease that out definitively.    

Which patients with CRC should receive molecular testing, and at what point?

  One of the tricky things from our study is to answer the question of which individuals need germline testing. We’ve historically recommended germline testing for any CRC patient who has a particularly strong family history of colon cancer; any colon cancer patient with a strong family history of endometrial cancer, ovarian cancer, and other cancers linked to Lynch syndrome; and any CRC patient who has a significant number of colorectal adenomas or other polyps.   


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