Mutually exclusive events in 294 cell lines (GSK set).

<p>In the potential space of double genomic events totaling 34191 co-events, we identified events that co-occurred less than expected by chance. These correspond to the extreme left tail of the distribution in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060339#pone-0060339-g002" target="_blank">Fig. 2</a>. Events that co-occur less than expected by chance are mutually exclusive (observed freq = 0; <b>BOLD</b>), or partially exclusive (observed freq>0). Events with the most significant P-values AND maximal differences are reported here. <i>Italics</i> indicate P-values [0.06–0.10].</p

Mutually exclusive events and co-occurring events in 294 cell lines (GSK set).

<p>Plot of the difference between the frequencies (<i>Observed – Predicted)</i> for all potential double genomic events in the 294 cell lines. Based on 262 distinct genes affected, there were a total of 34,191 potential genomic events involving two genes. Negative differences furthest from zero (left tail) are mutually exclusive events, positive differences furthest from zero (right tail) are co-selected events. The significant events from the left and right tails are found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060339#pone-0060339-t003" target="_blank">Table 3</a> and Table S5 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060339#pone.0060339.s003" target="_blank">File S3</a>.</p

Genomic co-events significantly associated with drug response to the MEK inhibitor GSK1120212.

<p>The top 30 significant single, double and triple genomic co-events are represented here. The frequency of the event in sensitive vs resistant lines is represented by a ratio. #DIV/0!/infinite denotes a strong association with sensitivity. Increasing association with sensitivity in cell lines is indicated by an increasing freq S/freq R ratio >1.5, and increasing association with resistance by a decreasing ratio <0.67, as shown. Top co-events where selected when they fulfilled the following 3 criteria: <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060339#pone.0060339-Druker1" target="_blank">[1]</a> most significant P-values (P< = 0.05), with <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060339#pone.0060339-Gorre1" target="_blank">[2]</a> the maximum number of cell lines harboring the event, and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060339#pone.0060339-Poulikakos1" target="_blank">[3]</a> an S/R ratio that was the furthest from unity in both directions.</p

Unsupervised hierarchical clustering of the sensitivity (GI values) of 310 cell lines to 37 targeted drugs.

<p>Each row represents a separate cell line, and each column represents a separate compound tested. Increasing sensitivity of a cell line is indicated by the increasing intensity of the green signal, and increasing resistance of a cell line is indicated by the increasing intensity of the red signal; black squares denote sensitivity close to the median across cell lines. Cell lines not screened with a particular compound are indicated in gray. The data from Fig. 3 is split into two less complex figures (Fig.S3 and S4 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060339#pone.0060339.s001" target="_blank">File S1</a>) to decrease noise and provide a better display of functional relationships and activated oncogenic pathway subclusters.</p

Cancer as a micro-evolutionary process.

<p>Illustrated here is a sequential multiple hit model of cancer initiation and progression, underlying co-selection and mutual exclusivity of genetic events in cancer. A, B, C are genes inside a cell’s nucleus. After a mutation occurs (marked by lightning strike), the progeny of a cell are subjected to selective pressures as illustrated in 1, 2, 3, 4, 5, 6 and 7. Mutations that provide a survival and proliferative advantage to the cell will lead to an increase of that cell and its gene pool in the population of cells. The cell with a mutation in gene C has an advantage over the cell with no mutation and it will outnumber the latter. The same applies to the cell with mutation in genes A or B respectively. Subsequently, the cell with sequential mutations in genes A and C has a proliferative advantage over the cells with either mutations A alone or C alone [7 and 2], and it will outnumber them; these cells carry advantageous co-mutations that are co-selected in the population. Conversely, the cell with mutations in B and C, even though each mutation on its own endows a proliferative advantage [4 and 1], is at a selective disadvantage as compared to cells with mutations in B only <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060339#pone.0060339-Chandarlapaty1" target="_blank">[5]</a>, or C only <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060339#pone.0060339-Poulikakos1" target="_blank">[3]</a>, and therefore will tend to disappear from the cell population; these cells harbor mutually exclusive co-events.</p