343genomic changes and their signifi cance for CRC tumorigenesis was lacking.
Genomic patterns that have now been uncovered in CRC, including samples origi-
nating at sites in either the colon or the rectum, reveal genomic profi les that are
similar to those present in tumors at each site (The Cancer Genome Atlas Network
2012 ). By doing sequencing, CNV analyses, and/or methylation profi ling on almost
300 CRC samples, the team narrowed in on key genes and pathways that tend to be
altered in CRC. For the new analysis, researchers used SOLiD or Illumina sequenc-
ing platforms to sequence the exomes of 224 tumor-normal pairs to an average
depth of >20 X over 80 % or more of the coding sequences targeted. With the
Illumina HiSeq 2000, they also did low coverage WGS on 97 of the tumors and
matched normal samples. The transcriptional analysis was expanded further through
RNA sequencing and miRNA sequencing experiments. The data presented provide
a useful resource for understanding CRC and identifying possibilities for treating it
in a targeted way. Although it may take years to translate this foundational genetic
data on CRC into new therapeutic strategies and surveillance methods, this genetic
information will be the springboard for determining what will be clinically effective
against CRC. A subset of the CRC, most often tumors showing up in the right or
ascending colon, had unusually high mutation levels. Approximately 16 % of the
tumors could be classifi ed as hypermutated, containing a median of 728 predicted
somatic mutations apiece.
More than 75 % of these hypermutated samples showed enhanced methylation
levels and microsatellite instability. As the survival rate of patients with high micro-
satellite instability-related cancers is better and these cancers are hypermutated,
mutation rate may be a better prognostic indicator.
From their genome sequence data, researchers tracked down several suspected
translocation events involving bits of sequence from different chromosomes. For
example, 3 of the 97 tumors assessed by low-coverage genome sequencing con-
tained a fusion linking the fi rst exons of the chromosome 11 gene NAV2 to part of
the chromosome 2 gene TCF7L1, which codes for a component in the WNT path-
way, a known contributor to CRC. Almost all of the tumors from both the hypermu-
tated and the non-hypermutated groups included mutations expected to boost the
activity of the WNT signaling pathway and to curb signaling via the TGF-β path-
way, changes that are expected to produce an increase in the activity of the MYC
proto-oncogene. These fi ndings fi t with early reports suggesting that compounds
targeting that pathway may be effective against some CRCs. Possible therapeutic
approaches to CRC included WNT-signaling inhibitors and small-molecule
β-catenin inhibitors, which are showing initial promise. Other commonly affected
pathways included the RTK-RAS, MAP kinase, TP53, and PI3 kinase pathways,
which point to potential targets for new CRC treatments. Approximately 5 % of the
CRC tumors studied had extra copies of a gene, ERBB2, as do many breast cancer
tumors. The drug, Herceptin, which is effective for breast cancer patients with too
many ERBB2 genes, might also help CRC patients with the same aberration.
Clinical trials have been proposed to test the effects of Herceptin in these CRC
patients. Approximately 15 % of CRCs had a mutation in a gene, BRAF that is also
often mutated in melanoma. A drug approved for melanoma blocks the function of
BRAF gene product, but it has not worked in CRC patients.
Personalized Management of Cancers of Various Organs