By Kevin E. Noonan ---
Somewhere between
This reticence was evident at the onset of the Human
Genome Project (HGP), and has come up again in the latest genome mapping
project: the Cancer Genome Atlas (TCGA). The goal of this project is to map mutations
in various human cancers, to identify cancer-specific changes in tumors,
including those in common between different tumors and those unique to
particular tumor types (such as breast cancer). Cancer etiology has been known to be associated with acquired mutation
since the work of Doll in the 1950's, and tumor cells themselves are
characterized by genetic instability, developing, for example, aneuploidy (an
abnormal number of chromosomes), chromosomal translocation (for example, the
Philadelphia chromosome in chronic myelogenous leukemia), and increased
mutation frequency. Besides building on
the success of the HGP strategy, the concept is a logical extension of work in
colon cancer over the past few decades, where specific genetic mutations have
been associated with risk for and ultimately developing colon cancer. The
strategy, and the fruits of the strategy, can be seen in a recent report by Greenman et al. on
colon cancer genetics in the journal Nature.
The dissenters argue that this is a waste of time and money,
and will prejudice funding for other projects (a complaint raised against the
HGP that did not in the event occur). The most important criticism is that the tumor tissue used for the
studies (biopsy and pathological samples from the primary tumor) will not
include the purportedly rare (1 in 50,000) "metastatic" cell, the
progenitor of the cells responsible for characterizing a tumor as
malignant. This cell, according to the
dissenters, arises early in tumorigenesis and has been dispersed from the primary
tumor site long before an individual is diagnosed with cancer; hence, the
"most important" mutations will be missed by TCGA. Moreover, the argument goes, the genetic
instability that causes increased mutation frequency in cancer cells will
render most of the detected mutations meaningless because they are not
"responsible" for cancer but are simply consequences of and
irrelevant to the tumorigenesis.
These issues, which are not trivial, seem to miss the
point. Even if a particular mutation
that is found to arise in many different cancer types is not "responsible"
for tumor development, its presence may provide a target for chemotherapeutic
intervention (particularly if the mutation renders the tumor cells much more
susceptible to the drug than normal cells). It is also possible that the primary tumor will bear traces of the
mutations responsible for metastasis, traces than can be correlated with
clinical outcomes that will provide clues to these elusive genes. Most importantly, just like the HGP, TCGA
will provide a wealth of data that, in the aggregate, are likely to provide
some surprising and unexpected insights into cancer cell biology, a result that
even the dissenters will be hard pressed to deny will advance our understanding
of the disease.
Tolstoy said "All happy families resemble one another; every unhappy family is unhappy in its own way." Whether cancer cells most resemble happy or unhappy families is but one of the expected consequences of TCGA and one that has the prospect of providing unexpected and useful information unlikely to be obtained any other way. For that reason alone it deserves support.
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