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Clear Cell Endometrial Cancer Genomics Reveal Mutations, Molecular Similarities to Other Subtypes

NEW YORK (GenomeWeb) – A new genomic study is highlighting the somatic mutation similarities — and differences — between clear cell endometrial cancer (CCEC) and other histological subtypes of endometrial carcinoma.

"Because the cancer is often diagnosed after it has spread beyond the uterus, the mortality rate is unacceptably high," senior author Daphne Bell, a cancer genetics and comparative genomics researcher at the National Human Genome Research Institute, said in a statement. "We're trying to build a knowledge base to decipher the fundamental genomic changes that drive these cancers."

Researchers from the US, Spain, and Norway used exome sequencing to profile somatic mutations in 16 CCEC tumors. As they reported today in the journal Cancer, the sequence data led to nearly two-dozen candidate genes that were subsequently profiled by targeted sequencing in 47 more CCEC cases. Across the complete tumor set, they identified frequently mutated genes and got a look at new genes with potential roles in CCEC, particularly the transcription factor complex subunit gene TAF1.

By profiling microsatellite stability and just a handful of genes, the group reported, it could detect CCEC subtypes resembling other forms of endometrial carcinoma: serous endometrial cancer or endometrioid endometrial cancer.

"Our findings implicate TAF1 as a novel candidate driver gene in a subset of cases," Bell and her co-authors wrote. "Moreover, we demonstrate that a substantial number of CCECs molecularly resemble either [serous endometrial cancer] or [endometrioid endometrial cancer]."

The team began by sequencing the protein-coding portions of the genome in fresh-frozen tumor samples from a dozen individuals with CCEC and the CCEC-like portion of tumors from four more individuals with mixed-histology tumors. It then compared these sequences to exome sequences from matched normal samples for each individual.

The researchers uncovered two tumors with markedly high mutational loads and microsatellite instability levels when they sifted through the data to find somatic mutations. The remaining microsatellite stable tumors harbored hundreds of non-synonymous or splice site mutations, leading to 222 genes that they took forward for further analysis.

From there, the team targeted 22 genes for Sanger sequencing in samples from another 47 individuals with CCEC, profiling the samples for microsatellite stability or instability — an analysis that made it possible to pick apart mutation frequencies for the recurrently affected genes in CCEC.

Nearly 40 percent of the CCEC tumors considered contained mutations affecting TP53, for example, while close to 25 percent had PIK3CA mutations. A smaller proportion of tumors had alterations impacting genes such as PIK3R1, ARID1A, PPP2R1A, SPOP, or TAF1.

When they considered the discovery and validation cases together, alongside existing genetic data for serous or endometrioid forms of endometrial carcinoma, the authors found that just seven genes could pick out CCEC tumors resembling the other subtypes when profiled in concert with microsatellite patterns.

Based on their results and those reported in past studies, they concluded that "the molecular features of CCECs are heterogeneous and overlap with those of SECs and EECs."