Research Article: Convergence of Mutation and Epigenetic Alterations Identifies Common Genes in Cancer That Predict for Poor Prognosis

Date Published: May 27, 2008

Publisher: Public Library of Science

Author(s): Timothy A Chan, Sabine Glockner, Joo Mi Yi, Wei Chen, Leander Van Neste, Leslie Cope, James G Herman, Victor Velculescu, Kornel E Schuebel, Nita Ahuja, Stephen B Baylin, Adi F Gazdar

Abstract: BackgroundThe identification and characterization of tumor suppressor genes has enhanced our
understanding of the biology of cancer and enabled the development of new diagnostic and
therapeutic modalities. Whereas in past decades, a handful of tumor suppressors have
been slowly identified using techniques such as linkage analysis, large-scale sequencing
of the cancer genome has enabled the rapid identification of a large number of genes
that are mutated in cancer. However, determining which of these many genes play key
roles in cancer development has proven challenging. Specifically, recent sequencing of
human breast and colon cancers has revealed a large number of somatic gene mutations,
but virtually all are heterozygous, occur at low frequency, and are tumor-type specific.
We hypothesize that key tumor suppressor genes in cancer may be subject to mutation or
hypermethylation.Methods and FindingsHere, we show that combined genetic and epigenetic analysis of these genes reveals many
with a higher putative tumor suppressor status than would otherwise be appreciated. At
least 36 of the 189 genes newly recognized to be mutated are targets of promoter CpG
island hypermethylation, often in both colon and breast cancer cell lines. Analyses of
primary tumors show that 18 of these genes are hypermethylated strictly in primary
cancers and often with an incidence that is much higher than for the mutations and which
is not restricted to a single tumor-type. In the identical breast cancer cell lines in
which the mutations were identified, hypermethylation is usually, but not always,
mutually exclusive from genetic changes for a given tumor, and there is a high incidence
of concomitant loss of expression. Sixteen out of 18 (89%) of these genes map
to loci deleted in human cancers. Lastly, and most importantly, the reduced expression
of a subset of these genes strongly correlates with poor clinical outcome.ConclusionsUsing an unbiased genome-wide approach, our analysis has enabled the discovery of a
number of clinically significant genes targeted by multiple modes of inactivation in
breast and colon cancer. Importantly, we demonstrate that a subset of these genes
predict strongly for poor clinical outcome. Our data define a set of genes that are
targeted by both genetic and epigenetic events, predict for clinical prognosis, and are
likely fundamentally important for cancer initiation or progression.

Partial Text: It is widely accepted that loss of tumor suppressor function leads to the initiation and
progression of human cancer [1,2]. Inactivation
of tumor suppressor genes can result from both genetic mechanisms such as mutation or
epigenetic mechanisms such as DNA hypermethylation [3–5]. Identification of these genes provides insight into the biological
processes underlying oncogenesis and is useful for developing new therapeutic and diagnostic
modalities. Recently, several efforts to examine the cancer genome utilizing large-scale
sequencing have revealed that a large number of genes undergo somatic mutation in cancer
[6,7]. Sjoblom et al. sequenced 13,023 human genes in
breast and colon cancer and identified 1,149 that harbored somatic mutations. Through
statistical analysis, they showed that the majority of these changes were passenger
mutations and that 189 genes were likely selected for during tumorigenesis (candidate cancer
genes [CAN]). Interestingly, for virtually all of the newly discovered
mutations, the frequencies in each tumor type were low—in the range of
5% to 15%. Furthermore, the vast majority of these mutations were
heterozygous missense mutations. Thus, it is difficult to know whether each mutation conveys
an oncogenic or tumor suppressor function. Moreover, if the genes are tumor suppressors, the
heterozygous nature of the mutations would provide loss of function effects through a state
of haploinsufficiency. This has been seen for a number of cancer genes including
APC and MSH2 [8,9]. It may also be possible that many of the heterozygous mutations are
dominant and oncogenic. Similarly, Greenman et al. demonstrated that the mutational spectrum
of protein kinases in tumors is highly variable and that mutations in a large number of
cancer genes are operative in human tumors [6]. Again, it is unknown whether most of the
mutated genes are oncogenes or tumor suppressors. Finally, most of the mutations identified
in breast cancers were not present in colon tumors and vice versa [7], suggesting that the mutational
spectrum is highly tumor-type specific.

Overall our study presents an extensive search for the presence of and interactions between
both genetic and epigenetic alterations in cancer. As it currently stands, these studies do
have several limitations. First, our data do not address the biological effects of the
individual mutations observed in the CAN genes. Second, the data draw on only the 13,023
subset of CCDS genes that were previously sequenced, and additional genes have now been
sequenced and more mutations have been discovered [42].

Source:

http://doi.org/10.1371/journal.pmed.0050114

 

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