Endometrial cancer is the fourth most common cancer for women in the United States and the sixth most common cause of cancer death. Unfortunately, the incidence of endometrial cancer is rising, most likely due to an increase in obesity, which is a significant risk factor for the disease.
One of the primary factors in the higher mortality rates for endometrial cancer is diagnosis. There is a need to detect these cancers at an earlier stage, however, there is no effective screening method available. Using information from the Cancer Genome Atlas that discovered sets of molecular defects and somatic mutations that define this cancer, researchers at Icahn School of Medicine at Mount Sinai hypothesized that earlier detection of these mutations could be possible using deep sequencing of DNA collected from a patient’s uterine lining.
"Today, there are no effective screening methods for endometrial cancer, which is increasing in both incidence and mortality in the United States," said Peter Dottino, MD, Director of Gynecologic Oncology at Mount Sinai Health System and one of the senior authors on the study. "We were therefore interested in the possibility of coupling newly developed genomic technologies with current treatment practices to develop a precision medicine assay for screening and early detection of this cancer."
The study, published in PLOS, was conducted on 107 women who were undergoing diagnostic procedures due to post-menopausal uterine bleeding or abnormal pelvic ultrasound results. Uterine cells and DNA were collected and analyzed using sets of targeted gene panels to sequence specific genes known to be associated with endometrial cancer development and progression. The samples were also subjected to standard analysis and molecular screening procedures.
The findings were consistent with standard analysis but the deep sequencing method also uncovered additional information not found with standard methods in about half of the patients. Seven of the women were diagnosed with endometrial cancer, receiving positive results in both standard histopathological methods and by deep sequencing. Results for the targeted panels showed significant cancer-driver mutations in these patients, confirming the method of diagnosis.
Interestingly, 51 women with no histopathological evidence of cancer also had positive cancer-driver mutations based on the new diagnostic method. The team was able to associate age and post-menopausal status with these mutations within all 51 of these women. These results indicate that deep sequencing of the uterine lining using targeted mutation panels can identify cancer or pre-cancer status, but cannot distinguish between the two.
Next steps are to examine the likelihood that these 51 women might get endometrial cancer based on their gene panel results and what factors might interrupt this pathway, leading to false positive results. Further analysis of the findings could increase understanding of how endometrial cancer is initiated in the uterine lining and why some women contract cancer while others do not.
"By discovering a previously unrecognized cancer gene mutation landscape in women both with and without cancer, this work represents a powerful opportunity to gain new insights into why some women remain healthy and cancer-free while others succumb to this disease," said Eric Schadt, PhD, the Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai, and Founding Director of the Icahn Institute for Genomics and Multiscale Biology. "Understanding why some women remain resilient to developing endometrial cancer has implications not only for this cancer but may possibly lead to greater understanding across many cancers."
