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Colorectal Cancer Tumors Marked by CNV Heterogeneity

NEW YORK (GenomeWeb) – A new study suggests that DNA copy number may vary within and between tumors from a given individual with colorectal cancer, even when protein-coding mutations remain relatively constant.

German researchers did targeted, deep sequencing on nearly 100 primary tumor and matched metastatic tumor samples from 27 individuals with CRC, focusing on DNA sequence mutations and CNV shifts affecting 100 cancer-related genes. Their results, published online today in Nature Communications, pointed to pronounced CNV variability from one tumor to the next. Such heterogeneity also turned up across dozens of samples from a single CRC tumor, hinting that an appreciation of CNVs patterns may complement information gained from DNA mutation profiling.

"This work indicates that regional differences in gene copy numbers are an important aspect of tumor heterogeneity in CRC," senior author Christine Sers, a pathology researcher affiliated with the Charité Universitätsmedizin Berlin and the German Cancer Consortium, and her co-authors wrote. "Our results thus propose implementation of broader clinical routines taking into account both DNA mutations and copy number changes."

Based on studies done so far, which suggest that CRC cases may be marked by heterogeneity, the team set out to more carefully explore the relationship between DNA mutations and CNVs within and across tumors in individuals with CRC.

Using the Life Technologies Ion Torrent PGM instrument, the researchers did targeted, massively parallel sequencing on 97 primary and metastatic tumor samples from 27 individuals with stage III or stage IV CRC, focusing on 100 genes with known or suspected roles in the disease. They followed up on apparent mutations or CNVs with Sanger sequencing, Illumina sequencing, and/or fluorescent in situ hybridization.

The team detected recurrent mutations in several genes, particularly TP53, APC, and KRAS. But between-tumor mutation differences in a given individual were relatively rare, turning up in just four of the CRC cases.

On the other hand, the researchers reported that CNV differences were quite common, not only between individual CRC cases, but also across primary and metastatic tumors from the same individual and between clusters of adjacent cells from the same tumor.

Likewise, when they sequenced dozens of samples from a single stage IIA CRC tumor, the investigators identified CNVs that varied depending on the tumor location considered, despite the presence of consistent TP53 and APC mutations.

"We found chromosomal aneuploidy and heterogeneity far more prevalent than hot-spot [single nucleotide variants] within driver oncogenes among multiple tumors between patients and within an individual patient," the authors wrote.

Even so, they cautioned that there may be DNA variants outside of the genes targeted for the current analysis that do vary more dramatically across and between tumors. "[W]ithin the limited genomic area the panel covers, some intronic and synonymous mutations show a heterogeneous pattern," they wrote. "This could indicate that genome-wide sequencing may additionally reveal clonal [single nucleotide variants], which our analysis does not cover."