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Endometrial Cancer Mutations Detected in Uterine Lavage Samples

NEW YORK (GenomeWeb) – A new study has confirmed that mutations linked to endometrial cancer can be identified in uterine lavage fluid, though the fact that these mutations can be present in women both with and without cancer must be investigated further before the findings might be clinically implemented.

Investigators led by John Martignetti of the Icahn School of Medicine at Mount Sinai, as well as scientists from Swift Biosciences, published the results in PLoS One this week, concluding that DNA analysis of lavage samples could help diagnose endometrial cancers, especially in cases where the histopathology is lacking. However, methods must be developed to reduce the risk of overdiagnosis implied by the team's current results.

Swift and its collaborators at Mount Sinai are not alone in their interest in detecting endometrial cancer using fluid samples from gynecologic procedures or examinations. Notably, a Johns Hopkins University team has been developing methods to detect endometrial and ovarian cancers from pap smears, or potentially even from samples taken from menstrual tampons.

"Since a uterine lavage can be easily and quickly performed in a physician’s office, our initial idea was that this molecular approach could lead to early detection of pre-cancerous and cancerous conditions of the uterus," Mount Sinai's Martignetti said in a statement regarding his team's recently published  PLoS One results.

In the prospective study, the team performed uterine lavage (a technique to rinse the inside of the uterus with saline fluid) on 107 women undergoing a hysteroscopy due to post-menopausal uterine bleeding or abnormal pelvic ultrasound results. The authors wrote that they specifically chose to take all comers, and did not concentrate the cohort in any way for women with known genetic risk factors or family history.

Working with Swift, the researchers then used targeted sequencing panels to analyze the lavage samples for mutations in genes known to be linked to endometrial cancer development and progression.

To establish baseline performance for the different sample types — cell-free DNA versus lavage-borne cells — the team first sequenced samples from nine patients using the Accel-Amplicon 56G Oncology Panel. Then, using the TCGA dataset for endometrial tumors and their associated mutational profiles, the group settled on a smaller custom amplicon panel to cover the 12 genes with the highest mutation frequencies in the rest of the cohort. These included PTEN, PIK3CA, TP53, CTNNB1, KRAS, FGFR2, FBXW7, RB1, ATM, APC, ARID1A, and PIK3R1.

In parallel to the genetic study, patients' hysteroscopy samples were also examined using traditional gold-standard histopathology methods, allowing researchers to compare the two.

Overall the team identified seven women with confirmed endometrial cancer based upon the histopathological evidence. All seven, even those with only microscopic evidence of cancer in their histopathology results, had mutations present in their uterine lavage fluid, both in isolated cells and in cell-free DNA.

However, the study also found known cancer driver mutations in 51 of the 95 women with no histopathological evidence of cancer or with benign diagnoses.

This means, first, that the presence of mutations in the genes targeted in the study can't be used alone as evidence for diagnosing cancer.

However, the finding also raises the question of whether these mutations may indicate some sort of pre-cancerous state. The researchers will have to investigate further by following women with positive mutation results but no histopathological evidence of cancer to see if or when they might develop cancer in the future.

According to the study authors, the most frequent driver mutations detected in the non-cancer group were in KRAS and PIK3CA. "The finding that a majority of women without a cancer diagnosis carried mutations, the relatively high allele fractions … and the projected oncogenic impact of these mutations was surprising," the group wrote. One patient, for example, had a decidedly benign diagnosis, yet showed mutations in lavage cells and cell-free DNA in a total of five genes, all of which the researchers confirmed using droplet digital PCR.

"Translating the findings from this precision oncology study to earlier cancer detection in women has the potential to transform current clinical care," study author John Murphy, President and CEO of the Western Connecticut Health Network, said in a statement.

However, the authors wrote, given the study results, "what may be most clinically relevant is identifying and understanding the mechanisms by which some clones continue to evolve and become cancer while others are halted."

"While successful screening for earlier detection of cancer will undoubtedly improve quality of life and improve survival, insights into halting the progression of steps linking somatic mutation and the evolution towards cancer provide the greatest benefits. These goals must be balanced by the harm that would currently be imposed by overdiagnosis," they added.

According to Martignetti, the team is now focused on a second phase of research with 1,000 women enrolled across multiple institutions to help begin sorting out these questions.