Molecular similarities discovered among endometrial cancers

Clear cell endometrial cancer appeared to have molecular similarities with serous endometrial cancer and endometrioid endometrial cancer, according to a study published in Cancer.

Additionally, researchers reported that TAF1 appears to be a driver mutated gene in clear cell endometrial cancer (CCEC).

Endometrial cancer is the fourth most common cancer and the sixth leading cause of cancer-related death in women in the United States. Endometrial carcinomas account for approximately 76,000 deaths annually worldwide.

Several research groups have reported the mutational landscape of serous endometrial cancer and endometrioid endometrial cancer, but the molecular etiology of CCEC has been poorly understood.

Daphne W. Bell, PhD, researcher at the National Human Genome Research Institute, and colleagues conducted exome sequencing of paired tumor-normal DNAs from 16 cases to interrogate the mutational landscape of CCEC. They also Sanger-sequenced 22 genes from another 47 cases of CCEC.

The researchers measured microsatellite instability and stability by genotyping five mononucleotide repeats.

Results showed two tumor exomes had relatively high mutational loads and microsatellite instability. The other 14 tumor exomes presented with microsatellite stability and had 236 validated nonsynonymous or splice junction somatic mutations among 222 protein-encoding genes.

Among the 63 cases of CCEC, researchers identified frequent somatic mutations in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%) and TAF1 (9.5%), as well as microsatellite instability (11.3%). Five of eight mutations in TAF1 — a gene with no known role in CCEC — localized in the putative histone acetyltransferase domain and included two recurrently mutated residues.

Thus, based on patterns of microsatellite instability and mutations in those seven genes, CCEC subsets molecularly resembled serous endometrial cancer or endometrioid endometrial cancer.

“We found CCEC to be more mutationally heterogenous than [serous or endometrioid endometrial cancer] across a series of seven genes and microsatellite instability as evidenced by shared patterns of alterations between CCEC and serous endometrial cancer, and CCEC and endometrioid endometrial cancer,” Bell and colleagues wrote. “Similarly, shared patterns of alteration are also observed when comparing the molecular features of CCEC in this study to those of [serous or endometrioid endometrial cancer] in The Cancer Genome Atlas Project.”

Researchers did not include a systematic pathology review of the discovery or prevalence of screen tumors and noted some of the molecular heterogeneity observed may reflect inaccurate histological classification.

“However, the aim of our study was not to provide a morphologic or molecular reclassification of CCEC,” Bell and colleagues wrote. “Rather, our findings reflect the molecular profiles of tumors from patients who were clinically diagnosed with CCEC or endometrial cancer with a CCEC component.”

Although the study provides new knowledge and insight into the molecular drivers of CCEC, it leaves a number of questions unanswered, Gloria S. Huang, MD, and Allesandro D. Santin, MD, gynecologic oncologists at Yale School of Medicine, wrote in an accompanying editorial.

“For example, what is the genetic heterogeneity among CCEC, and if subjected to genetic classification, would distinct subtypes emerge?” Huang and Santin wrote. “How similar or different is the genomic landscape of CCEC to other endometrial types and to other clear cell adenocarcinomas (eg, ovarian clear cell carcinoma, renal clear cell carcinoma)? To answer these questions will require additional molecular profiling of more patients.” – by Chuck Gormley

Disclosure: The Intramural Program of the National Human Genome Research Institute, NIH and others funded this study. The researchers, Huang and Santin report no relevant financial disclosures.