Zodiac (case 4): Gene Fusion

This is the 4th-article of a blog series aiming to introduce Zodiac, a comprehensive tool that reveals genetic interactions in cancer by big-data computation. An introduction of Zodiac is in the 1st article here.

Previously, I briefly introduced Zodiac and presented case 1 (here), case 2 (here), and case 3 (here). Case 4 is about gene fusion.

A gene fusion refers to a genetic event where two previously separated genes on the genome are formed as a hybrid gene by rearrangement, such as translocation. The most well-known fusion gene is the Philadelphia chromosome, which involves reciprocal translocation between chromosome 9 and chromosome 22, which is specifically designated t(9;22)(q34;q11). This results in an ABL-BCR fusion gene, a hybrid gene formed by two separate genes, ABL1 and BCR. ABL-BCR gene fusion is frequently observed in chronic myelogenous leukemia (CML), and leads to the development of drug Gleevac in the late 1990’s and early 2000’s, as one of the first targeted cancer therapies.

Since then, fusion genes have been haunted by scientists and their roles to diseases investigated. If two genes are fused, they act as one gene. Therefore, they are likely to be co-expressed (GE-GE interaction), co-copy-number-changed (CN-CN interaction), or co-methylated (ME-ME interaction). Since Zodiac provides information on all three types of interactions for any pairs of genes, it could lead to discoveries of novel gene fusions. Indeed, we have identified many and below is one example.

Zodiac shows significant positive edges between gene expressions (see figure below), copy numbers, and methylations of ESR1 and CCDC170.

Screen Shot 2015-06-05 at 2.16.13 PM

A recent study published in Nature Communications (Veeraraghavan et al., 2014) identifies recurrent rearrangements between the oestrogen receptor gene ESR1 and its neighbour CCDC170, which are enriched in the more aggressive and endocrine-resistant luminal B tumours. This fusion encodes amino-terminally truncated CCDC170 proteins (CCDC170), which in ER+ breast cancer cells leads to markedly increased cell motility and anchorage-independent growth, reduced endocrine sensitivity and enhanced xenograft tumour formation. Mechanistic studies suggest that CCDC170 engages Gab1 signalosome to potentiate growth factor signalling and enhance cell motility.

As to the famous ABL-BCR gene fusion, well, Zodiac also shows that the two genes have positive GE-GE and ME-ME edges, but with no CN-CN edge. This is only weak evidence supporting potential gene fusion events. Recall that Zodiac is based on analysis of 1,400+ samples across 11 cancer types in TCGA that do not include CML, and that ABL-BCR gene fusion is frequently seen in CML, this lack of evidence might not be a surprise.

In summary, looking for co-occurrence of GE-GE, CN-CN, ME-ME edges between a pair of genes in Zodiac might reveal novel gene fusion candidates in cancer.


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