by ecancer reporter Clare Sansom

Endometrial cancer is the name given to cancers that arise from the lining of the womb, or endometrium; it is the most common gynaecological cancer in western countries, with about 50,000 new cases occurring in the US each year.

Until now, endometrial cancers have been classified into two groups.

Type I or endometrioid tumours are hormone receptor positive, are more common in obese women and in the younger age groups, and have a good prognosis, whereas type II tumours are primarily serous, are more common in older, non-obese women and tend to have worse outcomes.

Subtype identification is important in therapy selection, as early stage serous tumours are best treated with adjuvant chemotherapy whereas adjuvant radiotherapy is used to treat other early stage tumours.

Many genes have been observed to be commonly mutated in endometrial tumours, and some of these are more closely linked with one subtype than with the other.

A large, multi-centre group of researchers from the US-based Cancer Genome Atlas Research Network has now performed an in-depth genomic analysis of endometrial carcinoma with the aim of furthering our understanding of the molecular basis of this disease.

Tumour samples and matched germline DNA were obtained from 373 patients with endometrial cancer; 307 of these were classified as endometrioid, 53 as serous and 13 of mixed histology.

A comprehensive, integrative analysis of the genomes, transcriptomes and proteomes of all the tumour samples was carried out, involving many independent sequencing centres and six different technology platforms.

Analysis of somatic copy number alterations in all but ten of the tumour samples grouped the tumours into four clusters.

Most of the serous and mixed histology tumours and about 12% of endometrioid tumours fell into a single cluster that could be characterised by a very high degree of copy number variation: the three other clusters, almost entirely comprised of endometrioid tumours, included one with very high non-synonymous mutation rates but very little copy number variation.

Patients with tumours in the “serous-like” cluster had significantly shorter progression free survival than those in the other three, whether their tumours had been classified as serous, endometrioid, or mixed.

Sequencing the exomes of 248 tumours and matched normal DNA confirmed that the samples could be classified in four groups, three largely endometrioid and one largely serous.

One endometrioid group comprising 17% of all tumours had an exceptionally high mutation rate of on average 232 x 10-6 mutations per megabase (Mb) of DNA; frequent mutations in the gene POLE, which encodes a protein subunit involved in DNA replication and repair; and an association with good prognosis. 

The second endometrioid group had a lower mutation rate (18 x 10-6 mutations per Mb) and a high level of microsatellite instability (MSI) whereas the third group had a much lower mutation frequency of 2.9 x 10-6 mutations per Mb.

The serous cancers and those few endometrioid cancers that clustered with them, which had the highest level of copy number variation, also had a lower mutation frequency than any of the other groups.

The four clusters were termed, respectively, POLE ultramutated; microsatellite instability (MSI) hypermutated; copy number low; and copy number high, with the last named equivalent to the “serous-like” cluster.

Further analysis of mRNA expression, protein expression, microRNA expression and DNA methylation in all tumours led to the identification of signature genes and pathways that were dysregulated in each of the clusters.

Most of the signature genes of the POLE cluster were found to be involved in cellular metabolism, whereas the MSI cluster was characterised by decreased mRNA expression of a gene associated with colon cancer, MLH1: this was thought to be due to promoter methylation.

Tumours classified in the copy number low cluster were characterised by increases in progesterone receptor expression, indicating that these tumours might respond to hormone therapy.

The “serous-like” or copy number high cluster of tumours showed the most frequent mutations in TP53 and in genes associated with cell cycle regulation such as CCNE1, PIK3CA, MYC and CDKN2A.

Analysis of the serous and serous-like tumours also showed that these tumours shared many molecular characteristics with both high grade serous ovarian carcinoma and basal-like breast cancer, indicating that treatments developed for either of these cancers may also be appropriate for these endometrial tumours.

The results of this comprehensive analysis of endometrial tumours may help clinical decision making, and particularly in determining the best options after surgery for women with aggressive tumours.

Reference

The Cancer Genome Atlas Research Network (2013). Integrated genomic characterization of endometrial carcinoma. Nature 497, 67-73. doi:10.1038/nature12113