Out in the real world it’s common to hear people talk about
cancer as one disease.
But in the
scientific community, cancer is not one disease; it is many.
Each cancer type, each patient is
unique.
It’s part of the inherent
complexity of cancer.
And so cancer
scientists spend their time characterizing different tumor types to determine
their intrinsic similarities and differences.
These similarities and differences can – hopefully – be exploited to
tailor treatments for each specific disease.
A recent publication in
Nature,
as part of a larger initiative to understand the cancer genome, focuses on
these similarities and differences by outlining the mutational landscape across
12 major cancer types (
Find article here)
(1).
The methods are relatively straightforward. The researchers took 3281 tumors representing
12 different cancer types including breast, two different types of lung cancer,
colon, kidney, bladder, ovarian cancers, as well as acute myelogenous leukemia
(AML) among others, extracted and purified the DNA, and then subsequently
sequenced each tumor DNA sample. Since
we already know the sequence of the human genome, they compared these tumor
samples to matched normal tissue to identify regions, or specific genes, where
alterations such as mutations or small insertions or deletions, occurred. Using powerful software and statistical
methods, they investigated the mutational frequency for each cancer as well as
identified common and/or unique genes that were mutated.
As expected, these 12 major cancer types differ
genetically. Importantly, they also
share some similarities.
Similarities:
The principal result generated from this study was the
identification of 127 significantly mutated genes involved in a broad array of cellular
functions including some of the obvious functions such as DNA repair, cell
cycle control, and regulation of known key signaling transduction pathways
including the MAPK pathway and TGFb
pathways as well as less understood roles such as metabolism, histone
modification and proteolysis. Two things
become apparent from this list of genes and their functions: 1) The list is
small. Of the ~25000 genes in the human
genome, only 127 genes make the list of significantly mutated genes in
different cancer types. What makes these
genes primary targets for mutagenesis?
I’m not sure we know the answer to that question. 2) Although the list
of mutated genes is small, the functions they perform are broad and cover most
of the processes necessary for maintaining homeostasis, highlighting the
importance of maintaining cellular homeostasis for disease avoidance. Dysregulation of these cellular functions
leads to tumor progression no matter the cancer type.
Of these 127 SMGs, several of them can be found across multiple
cancers. The most commonly mutated gene, not surprisingly, is TP53, occurring in 42% of samples. We’ve known about TP53 for many years now and the vital role it plays as a tumor
suppressor by functioning as a transcription factor to control cell proliferation
and apoptosis. Next to TP53 is PIK3CA, which is mutated in greater than 10% of samples. This gene codes for a subunit of the P13K
protein which is essential for maintaining cell survival through induction of
cell growth and inhibition of cell death.
The fact that these genes, among other, become mutated in many cancers
suggests that these proteins are vital for maintaining cellular
homeostasis. Can they serve as therapeutic
targets?
Differences
Although some overarching themes emerge that characterize
cancer as a whole, the specific details defining each cancer are unique. For example, the mutation frequency varies
between tumor types, with AML having the fewest mutations and lung squamous
cell carcinoma having the highest. Not
only does the mutation frequency differ, but the types of mutations are also
different between cancer types.
Together, this suggests that factors other than age could contribute to
the development of certain cancers. For
example, a certain type of mutation called a C>A transversion is most common
in lung cancer, and not surprisingly, this type of mutation can be caused by
cigarette smoke.
More specifically, different tumors have different mutation
signatures. In other words, each cancer
has different genes and their encoded proteins altered. This is not a new concept, but this study
takes this idea a step further by identifying driver mutations in different
tumor types. Driver mutations are
identified by their early appearance in the progression of cancer and in their
ability to provide the cancer cell with a selective advantage for continued
growth. By looking at the variant allele
fraction (or the fraction of alleles that carry a mutation, VAF), the
researchers assumed that genes with high VAF in specific cancers could be
considered driver mutations. The tumor
suppressor TP53 has a high VAF across
tumor types suggesting mutations in this gene are universal for driving cancer
progression. However, other genes differ
in different tumor types. In breast cancer,
AKT1, CBFB, MAP2K4, ARID1A, FOXA1, and
PIKCA carry mutations, whereas PIK3CA,
PIK3R1, PTEN, FOXA2, ARIK1A are mutated in endometrial cancer.
Furthermore, even within each tumor type, specific clusters
can be separated out based on genetic signatures. Therefore, not only do cancer differ, but
variability also exists within that cancer type. Thus, even breast cancer is more than one
disease!
Where do we go from here?
I would not characterize this publication as one that
identified novel concepts in cancer research.
We already knew that cancer is complex and differs by type. However, by systematically analyzing the
mutational landscape across 12 different cancer types, this study identified
key genes and pathways involved in tumor progression.
At a scientific level, it is clear where this study should
go. We need to look at the list of 127
significantly mutated genes and assess their ability to act as therapeutic
targets for cancer treatments. Some of
these can already be effectively targeted in cancer treatments including EGFR
(Cetuximab, Lapatinab, for example) (2). Moreover, the identification of rational drug
combinations, targeting two of the key pathways identified in this study, may
help to avoid drug resistance and disease recurrence.
At a more personal level, you could consider the
implications of knowing your gene signature.
If you knew you carried a “driver mutation”, what would you do? With companies, particularly in the United
States, (23andMe) (3) offering to sequence your genome, the ability to
do this is a realistic possibility albeit at a high financial cost. In certain instances, for example in
hereditary breast and ovarian cancer, knowing that you carry a BRCA1/2 mutation
could cause you to undergo a radical mastectomy or hysterectomy. Carrying a BRCA1 mutation prompted Angelina
Jolie to undergo such a procedure. What
would you do?
Uncovered cancer morse for today: cancer is complex: it is not merely one disease but a group of related yet distinct diseases.
References:
1.
Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance
across 12 major cancer types. Nature.
2013;502(7471):333-339. doi: 10.1038/nature12634; 10.1038/nature12634.
2.
Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM. Molecular mechanisms
of resistance to therapies targeting the epidermal growth factor receptor. Clin Cancer Res. 2005;11(1):397-405.
3.
https://www.23andme.com/. Updated 2013.
