Targeted Colorectal Cancer Sequencing Leads to Potential Prognostic Role for APC Gene

NEW YORK (GenomeWeb) – A new study in Nature Communications has highlighted a set of genes that, when mutated, appear to provide clues to colorectal cancer outcomes.

Researchers from the Moffitt Cancer Center, the Gibbs Cancer Center, and elsewhere did targeted panel sequencing on nearly 500 colorectal cancer samples, focusing on more than 1,300 genes with known or suspected cancer roles. After folding in patient survival information, they identified 17 potentially informative genes that were mutated at frequencies resembling those reported for CRC tumors in the Cancer Genome Atlas.

Mutations involving the APC gene appeared to be particularly informative, prompting the team to come up with five mutation classes based on tumors with wild type APC or with one or more APC mutations.

"[W]e have developed a prognostic, five-class multigene mutation classification system for CRC, with APC playing a central role" the study's author wrote. "We believe that routine clinical APC mutation assessment, in addition to other known classifiers BRAF, KRAS, and TP53, is useful and expedient in predicting outcomes and may ultimately help improve the resolution of appropriate therapy by identifying high- versus low-risk sub-populations."

Using a combination of SureSelect targeted capture and Illumina GAIIx sequencing at BGI-Shenzhen, the researchers searched for prognostically informative mutations affecting 1,321 genes in 468 CRC samples. The same tumors were also profiled following Bethesda panel guidelines to determine whether they were high or low in microsatellite instability, or MSI.

As reported previously, prognoses were generally better for tumors classified as MSI-high — about 13 percent of those profiled for the analysis. Even so, survival dipped for cases involving MSI-high tumors containing BRAF mutations.

In the microsatellite stable tumors (MSS), meanwhile, the researchers saw three genes with significant ties to metastasis: APC, TP53, and KRAS. Tumors containing mutations in all three genes appeared relatively aggressive, they noted, undergoing metastasis more than one-fifth of the time in the CRC cases considered.

Outcomes were particularly poor for cases with two APC mutations in combination with mutations in KRAS and TP53. On the other hand, the team noted that tumors with one APC mutation — either alone or in combination with either mutant KRAS or TP53 genes — were linked to better survival times than tumors without any alterations to APC.

From these and other mutational patterns in the tumors, the team came up with an APC-based classification scheme for CRC that included five mutational groups with zero, one, or two APC mutations in combination with KRAS and TP53 changes. 

The authors noted that "identification of the new prognostic role of APC may be attributed to a more detailed mutational analysis and to a larger sample size."

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