Abstract
Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5) of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over-expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous ovarian cancers we provide a novel strategy for targeted therapeutic intervention.
Highlights
The management of ovarian cancer is in transition
Molecular subtypes of High-grade serous ovarian cancers (HG-SOC) We developed a classifier based on the molecular subtypes (C1, C2, C4, C5) identified in our previous study of 215 tumours from the Australian Ovarian Cancer Study (AOCS) [5]
We note that there was some variation in the relative frequency of the molecular subtypes in the different datasets and this may be associated with differences in the inclusion criteria used in each study
Summary
It is increasingly apparent that ovarian cancer is a complex series of distinct tumour types [1], requiring therapies that target molecular features common to the subtypes of the disease. Gene expression profiling revealed unappreciated diversity within HG-SOC by delineating four distinct molecular subtypes. Tumours with the C2 signature were characterised by intratumoural infiltration of immune cells, while C4 tumours had a relatively low expression of stromal genes and high levels of circulating CA125. The C5 subtype reflected a mesenchymal cell gene expression signature, and these tumours had sparse immune cell infiltration and were associated with low levels of circulating CA125 [5]. The genetic events that give rise to each molecular subtype of HG-SOC and control their clinical behaviour are currently unknown
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