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Cidon. J Unexplored Med Data 2018;3:8 I http://dx.doi.org/10.20517/2572-8180.2018.03 Page 3 of 16

This pathway shows alterations in chromosome numbers (aneuploidy) or heterozygosity damage and it is the
result of faults in chromosomal segregation, DNA damage response, etc.

Karyotypic alterations and the collection of crucial genes mutations are needed for cancer to originate and
to progress.

Chromosomal translocations, a transfer of genes between chromosomes, can promote neoplasias but some
could also be targeted by new therapies. One recurrent translocation involves TTC28 on chromosome 22 and
it is known that when this TTC28 becomes inactive (this have been seen in around 22% of cases), its role as
inhibitor of cancer growth is lost.

MUTATIONAL LOAD
[16]
Genomic instability in colon cancer places this tumour on the average group of mutation load , however,
some cases have a high rate of mutations. These are characterized by alterations in MMR genes leading
to microsatellite instability high (MSI-H) which is present in only some of colon neoplasias as mentioned
above, and its incidence reduces with more advanced stages. As such, it has been reported in 22%, 12% and 3%
[17]
of stages II, III and IV .

Somatic mutations in the exonuclease of polymerase epsilon catalytic subunit (POLE) although not frequent
in advanced colon cancers, have been reported in microsatellite stable (MSS) and hypermutated tumours.

These change the function of POLE at DNA replication leading to wrong bases introduction although more
[18]
needs to be done to know the biological implications of these changes. The key point is that tumours with
high load of mutations are important for immunotherapy.

CONSENSUS MOLECULAR SUBTYPES IN COLON CANCERS
As described, colon neoplasia is a very heterogeneous disease with different molecular mistakes leading to
the classification in four molecular subtypes [consensus molecular subtypes (CMS)] with different patient
outcomes.

CMS1 is present in 14% of the cases and it shows strong immune activation. Tumours are hypermutated,
[19]
with BRAF mutations, MSI and CpG island methylator phenotype (CIMP) .
CMS2, in 37% of the cases is a subtype that shows APC mutations and a significant activation of MYC and
[19]
Wnt signalling .
[19]
CMS3, in 13%, shows CIMP low, metabolic dysregulation and KRAS mutations .

And CMS4, in 23%, mesenchymal, with transforming growth factor-β activation, angiogenesis and invasion
[19]
of the stroma and it has also been correlated with worse overall survival (OS) .

Finally a mixed group, which is present in 13% of the cases and represents a transition phenotype or just
[19]
intratumoral heterogeneity .

CMS1 tumours express specific genes to cytotoxic lymphocytes making them potentially susceptible to
immune checkpoint inhibition.

CMS4 shows lymphocytic and monocytic markers with an immunosuppressive and inflammatory profile with
a significant infiltration of fibroblasts. These tumours will need a treatment targeting monocytes and cytokines.