Microsatellite Instability Common In Interval Colorectal Cancers

Microsatellite Instability Common In Interval Colorectal Cancers

Interval colorectal cancers are four times more likely than those detected by colonoscopy to harbor markers of genetic instability, according to a recent study, indicating that these lesions may develop faster than conventional colorectal cancer and clinicians may not be simply missing them.

The results come from a population-based study of all Utah residents diagnosed with CRC over a 14-year period. The researchers reported the findings at the 2018 Digestive Disease Week (abstract 729).

“The signal for microsatellite instability [MSI] was very strong and is consistent with other studies. I think there are unique biological differences, and MSI-H [MSI-high] status clearly stands out,” said N. Jewel Samadder, MD, of Mayo Clinic in Scottsdale, Ariz., who led the research. “MSI, even in sporadic cancers, may suggest there’s quicker development of tumors.”

The categories of “high” or “low/stable” MSI refer to the ability of cells to repair defective DNA. Tumors with high instability are more likely inherited—such as in Lynch syndrome—or are associated with methylation of certain genes in the cancer. MSI-high cancers tend to be more responsive to certain types of chemotherapy, Dr. Samadder said.

Interval CRCs, defined as cancers diagnosed within three to five years of a colonoscopy, have an estimated prevalence between 3% and 4%. The Utah study found a prevalence of 6%, which “practically speaking” matched figures other researchers have reported, he said.

The main point, he emphasized, is that regardless of prevalence, interval and detected cancers have unique biological features. “It’s not just operator error. It’s not just bowel prep. There are biological factors,” he said.

Dr. Samadder and his colleagues sought to identify distinct features that may play a role in the development of interval cancers. An earlier study from Minnesota analyzed 131 detected CRCs and 63 interval cancers, and found high levels of MSI-H and CpG island methylation phenotype (CIMP) in interval lesions. No difference in survival was found between the two populations (Am J Gastroenterol 2010;105[5]:1189-1195).

The Nurses and Health Professionals Cohort Study also found twofold elevations in MSI-H status and CIMP in interval lesions. Other studies have found higher rates of mismatch repair deficiency and Lynch syndrome—all implying a unique biological scenario. All of these previous studies, however, have limitations that render them not completely generalizable to the U.S. population or to routine practice, Dr. Samadder said.

Within a population-based, cross-sectional study of incident CRC cases in Utah (1995-2009), the researchers identified interval cancers as those developing within five years of a completed colonoscopy. Cases were frequency matched in a 1:1 ratio on age, sex and hospital site of diagnosis to detected cancers (defined as CRC diagnosed on a patient’s first recorded colonoscopy).

Archived specimens were retrieved and tested for MSI, CIMP, KRAS and BRAFstatus. Tumors were labeled as CIMP-positive if at least three of five gene markers were hypermethylated, and low or negative if zero to two genes were hypermethylated.

The search revealed 126,936 men and women undergoing colonoscopy, in whom 2,659 cases of CRC were diagnosed within the 14-year study period. Of these cases, 159 were defined as interval cancers (6%) and 2,500 were detected CRC (94%). For 84 interval CRC cases, archived tissue was available and was matched with tissue from 84 subjects with detected cancer.

The Interval Difference

Interval CRCs were more likely than detected CRC to occur in the proximal colon (64% vs. 44%; P=0.018) and to be at an earlier disease stage (85.7% vs. 69%; P=0.03). Demographic factors were similar in the two groups of patients, Dr. Samadder said.

Roughly one-third of patients with interval cancers (32%) had MSI-H compared with 13% of those with detected tumors (P=0.005), according to the researchers. In the multivariable logistic regression analysis of molecular predictors, MSI-H carried an odds ratio of 4.20 (P=0.002) for its association with interval cancers.

Survival rates five years after diagnosis did not vary between the two groups, including when stratified by molecular markers. The other molecular features—CIMP and mutations in BRAF and KRAS—appeared in similar frequencies for both interval and detected CRCs, indicating no differences in the serrated pathway between the groups.


“We have recently learned that about 15% to 30% of CRC develops through alternate pathways, including MSI and the serrated pathway that is best defined by CIMP,” Dr. Samadder said. “We didn’t find an association with the serrated pathway, though some studies have. These different pathways of tumorigenesis are important; serrated and MSI pathways may be the ones that lead to missed lesions.”

The researchers are still determining what percentage of MSI-H tumors also have BRAF mutations and CIMP, and will report these data later, he said.

Dr. Samadder noted that this is the largest population-based study of interval CRC in the United States and that the diagnosis of CRC was confirmed with the Utah Cancer Registry. As a result, the findings are generalizable “across the nation. This is one of the few population-based studies of interval cancer in the United States and provides a statewide comparison of descriptive and molecular features of interval and detected CRC,” he said.

Limitations of the research are the inability to exclude hereditary cancer syndromes; that subjects undergoing colonoscopy for reasons other than screening were included; and that archived tissue was available for only about half the subjects. However, subgroup analyses found no differences between the cases that were retrieved and those that were not available for tissue retrieval in terms of demographics, tumor stage or colon site, Dr. Samadder added.

Don’t Rule Out Serrated Pathway

Roy Soetikno, MD, MS, of the Universitas of Indonesia, in Jakarta, an expert in interval CRC, applauded the investigators for advancing the field’s knowledge of post-colonoscopy cancers.

In 2008, Dr. Soetikno and his colleagues reported that flat and depressed colorectal neoplasms are more common and conveyed greater risk for progression than had previously been believed (JAMA 2008;299[9]:1027-1035).These neoplasms can be challenging to detect and may be missed during colonoscopies, and lead to missed cancers, he said.

“Since the time of that publication,” said Dr. Soetikno, “the ssA/P [sessile serrated adenoma/polyp], which can also be difficult to detect, has been added as another potential etiological factor for post-colonoscopy CRC. Approximately one-third of the missed cancers in this study might have started as an ssA/P lesion.”

—Clinical Oncology News Staff

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