Genes of colon cancer recurrence differs among blacks, whites and Asians

The genetic makeup of colon cancer tumors and survival rates for patients with the disease differ by race, according to a study from researchers at the Mayo Clinic Cancer Center, published in the Journal of the National Cancer Institute.

These findings put the issue of race more prominently on the radar of investigators that cancer biology may contribute to race-based disparities,” says the study’s co-lead author, Harry Yoon, M.D., an oncologist at Mayo Clinic. “While it is too early to change the way we treat these patients, our results indicate that future studies are needed to examine potential biological drivers of these differences more closely.

According to the American Cancer Society, colon cancer is the third most common cancer in both men and women with more than 93,000 cases estimated to be diagnosed in 2015. Researchers have long known that blacks develop colon cancer at an earlier age and blacks with colon cancer are at higher risk of dying than whites. However, it has been difficult to identify why the differences in survival exist.

Researchers analyzed data from a large clinical trial of more than 3,000 patients with stage III colon cancer. The analysis revealed that tumors from whites, blacks, and Asians had different frequencies of mutations in two key cancer-related genes, BRAF and KRAS, which have been associated with worse outcomes. It also found that colon cancers were twice as likely to recur in black patients as in whites; however, the discrepancy was only evident in those under age 50.

Some of the potential reasons for this disparity include socio-economic factors, such as diagnosis at a later stage, decreased access to health care and suboptimal treatment.

The role of the biology of colon tumors according to race has not been examined as extensively,” says Dr. Yoon. “This biology can be reflected in the genetic makeup of tumors, as well as by whether and how quickly cancer returns after the patient has been treated.”

Dr. Yoon and his colleagues focused their efforts on finding out if colon cancers are genetically different based on race, as well as if race-based differences exist in recurrence rates. To do this, they examined data from a large clinical trial – Alliance N0147 – which included patients with stage III colon cancer from many centers in North America who all underwent surgery to remove their cancer and chemotherapy after surgery.

As part of the trial, the patients provided a self-description of their race as either white, Asian, or black or African-American. The researchers then evaluated the tumors from these participants to see if a mutation was present in the cancer-related genes BRAF and KRAS. They also noted if the cancer had returned after treatment.

Analysis of the data showed that tumors from whites, blacks and Asians were different in terms of the frequency of mutations in the BRAF and KRAS genes. Tumors from whites were twice as likely to have BRAF mutations; whereas, tumors from blacks had the highest frequency of KRAS mutations. Tumors from Asians were the most likely to have normal copies of both genes.

The analysis also indicated that the colon cancers among blacks had more than double the risk of cancer recurrence, compared to whites. However, this discrepancy was only visible among young patients – those under age 50. Almost half of younger black patients experienced colon cancer recurrence within five years, compared to only 22 to 35 percent of whites or Asian patients of any age.

This difference could not be explained by the genetic mutations most frequently found in the tumors of the different races. The researchers adjusted for a number of other potential confounders, such as tumor grade, the degree of lymph node involvement, depth of tumor invasion, body mass index, location of the tumor within the colon, history of smoking, and anomalies in mismatch repair genes; however, none seemed to affect the outcome for young blacks.

Because all patients were treated and had their disease monitored in a clinical trial,” says Dr. Yoon, “suboptimal treatment, differences in cancer stage, or reduced access to care cannot adequately explain the disparity.”

“In addition to published data indicating that a limited number of genes are preferentially mutated in colon cancers from black versus white patients, our study revealed differences in the mutation frequencies of BRAF and KRAS oncogenes that provide prognostic information in colon cancer patients,” says Frank Sinicrope, M.D., an oncologist at Mayo Clinic and co-lead author. “Our data provide further evidence that colon cancers from blacks are intrinsically different and are associated with more aggressive clinical behavior in young black patients.

​Yoon et al. Racial Differences in BRAF/KRAS Mutation Rates and Survival in Stage III Colon Cancer Patients. J Natl Cancer Inst. 2015; 107 (10): djv186 doi:10.1093/jnci/djv186 [Abstract]

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New colon cancer culprit found in gut microbiome

Changes in the gut bacteria of colon cancer patients indicate that some virulent bacteria could be linked to the progression of the disease, according to research published in the open access journal Genome Medicine. The findings could eventually be used to identify a virulence signature in these cancers and help doctors predict how bacterial changes in patients’ guts could affect their prognosis.

The human gut microbiome, the collection of microorganisms, their genomes and habitat that contributes to maintaining a healthy intestine, is thought to play an active role in colon cancer progression. Previous studies have shown that changes in the bacterial community occur in the gut microbiome of colon cancer patients, with tumors harboring increased bacterial diversity and an abundance of pathogenic bacteria compared to surrounding healthy tissue.

Although researchers have uncovered a variety of potentially pathogenic bacteria associated with colon cancer, little work has been done to determine if there is a single signature that might unify their findings.

Lead author Michael Burns from The University of Minnesota, USA, said: “It was surprising that the results were so clear. We were able to clearly identify the presence of two virulent strains of bacteria, including the discovery of a new potential culprit, Providencia.

This has obvious implications for colon cancer patients and by analyzing the similarities among these pathogens, we have uncovered a single signature of colon cancer when analyzing the gut microbiome that might help researchers identify these cancers in the future.”

This was the first study to focus on the pathogenic potential of the bacterial genes present in the colon cancer ‘tumor microenvironment’, the environment of surrounding blood vessels, immune cells and other cells. The genes of the gut microbiomes were predicted in 44 primary tumor and 44 patient-matched normal colon tissues to analyze the general microbial function.

The team in Ran Blekhman’s lab noted changes in the abundances of helpful, harmless, and pathogenic bacteria, including Fusobacterium and Providencia. Fusobacterium has previously been implicated as a cancer-causing group of bacteria, but this is the first time that Providencia has been linked to colon cancer.

Analyzing the major changes that take place in the gut microbiome could help researchers categorize the role particular bacteria play and identify the key players.

Additionally, by showing that the microbial genes predicted to be present in colon cancer tissue are enriched for virulence functions, clinicians could use this signature to uncover what bacterial changes in the gut mean for a patient’s health.

At this stage, the research cannot determine a definite causal link between Providencia species and colon cancer. While the study’s methods are robust for analyzing human gut samples, more research will be needed to assess the interactions between gut bacteria and the progression and development of colon cancer.

Burns et al. Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment. Genome Medicine. 2015;EPub Ahead of Print. doi:10.1186/s13073-015-0177-8 [Abstract provisional pdf also available]

Study sheds light on racial disparity in colon cancer

African-Americans half as likely to have genetic marker linked to better survival

African-Americans with colon cancer are half as likely as Caucasian patients to have a type of colon cancer that is linked to better outcomes. The finding may provide insight into why African-Americans are more likely to die of colon cancer than Caucasians with the same stage of disease.

The population-based study of 503 people with colon cancer found that 14 percent of Caucasians and 7 percent of African-Americans had a genetic marker called microsatellite instability, or MSI. These types of tumors are known to be resistant to the chemotherapy drug 5FU. Yet, even without chemotherapy, these patients tend to have better outcomes.

We know that patients with MSI colon cancer do better without chemotherapy. But these improved survival benefits are limited among African-Americans with colon cancer,” says lead study author John M. Carethers, M.D., John G. Searle Professor and Chair of internal medicine at the University of Michigan Medical School.

Results of the study appear in the journal PLOS ONE.

The researchers identified patients through the North Carolina Colon Cancer Study, a population-based, case-control study conducted throughout central and eastern North Carolina. The North Carolina study includes both rural and urban areas, creating adequate representation by African-American and rural residents.

The group of patients Carethers and his colleagues looked at was 45 percent African-American and 55 percent Caucasian. Researchers examined tissue samples taken at the time of surgery and assessed it for various markers, including MSI.

In addition to the racial imbalance in MSI, the researchers also found that African-Americans patients were more likely than Caucasian patients to have cancer on the right side of their colon. This is significant because right-sided colon cancer is easier to miss with screening and more likely to be found larger or more advanced than left-sided cancers.

Right-sided colon cancer may be the ‘black ice’ of the colon – unseen but potentially deadly. Strategies to better recognize and detect right-sided cancer may need to be pursued in a broader fashion,” Carethers says.

Carethers et al., (2014) Influence of Race on Microsatellite Instability and CD8+ T Cell Infiltration in Colon Cancer. PLoS ONE, 9(6): e100461. doi:10.1371/journal.pone.0100461 [Article]