Rare Mutations in Immune-Related Genes Linked to Multiple Simultaneous Colorectal Cancer Tumors

Genetic mutations affecting the immune system were identified in patients who develop more than one colorectal cancer (CRC) tumor at the same time. The researchers suggest that understanding how these cancers develop could improve therapy targeting.1

For most patients with CRC, one primary tumor develops then it may spread. However, in just 2% to 5% of cases, 2 primary tumors originate and develop independently, which is known as synchronous CRC.

This study analyzed 20 synchronous CRCs from 10 patients and compared their genetics to that of patients with only 1 CRC and to healthy people.

The synchronous tumors were found to be unrelated, as they had a variety of different genetic mutations that led to the cancer. This genetic variation makes synchronous CRCs more difficult to treat, as the differing targets may not be affected by the same targeted therapies.

Furthermore, the patients with synchronous CRC had more inherited damaging mutations in immune-related genes, with three-quarters of the patients with synchronous CRC having rare damaging mutations in genes related to immune system function.

The patients with synchronous CRC had differences in the composition of their gut immune cells. The authors explained that this could lead to gut inflammation, which could increase the frequency of independent cancer-initiating events.

“Prior to this study, it was unclear whether these multiple [synchronous] tumors started because of the same faulty genes. Now we know that these tumors are as different as cancers from 2 different people and patients inherit mutations in genes of the immune system that potentially have damaging effect,” said senior author Francesca Ciccarelli, PhD, Division of Cancer Studies at King's College London, United Kingdom. “These mutations are usually very rare in healthy people, but they occur at a much higher frequency in this patient group.”

Although CRC patients with synchronous tumors currently receive the same treatments as other cancer patients, Ciccarelli explained that their multiple tumors should receive tailored therapy because treatment response and resistance are likely to differ for each tumor.

Matteo Cereda, MD, Division of Cancer Studies at King's College London, and first author of the study, said, “These patients also have an abnormal composition of immune cells of the gut and in the tumors. Our hypothesis is that these individuals develop multiple tumors because they have an abnormal immune and inflammatory response that favors tumor initiation.”

Reference

1. Cereda M, Gambardella G, Benedetti L, et al. Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes. Nat Commun. doi:10.1038/ncomms12072. [Epub ahead of print]

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