Study findings better define the genetic landscape of neuroendocrine tumors of the cervix

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In an ambitious new study, a research team that included scientists from Yale set out to uncover potential treatments for patients with rare neuroendocrine tumors of the cervix (NETc) by understanding the molecular basis of the aggressive disease.

Currently, the average survival for patients diagnosed with NETc is less than two years.

For the study, which involved patients from across the world, Yale Cancer Center (YCC) researchers at Yale School of Medicine (YSM) analyzed the genetic landscape of 66 tumors, the largest series of cervical NET ever reported in scientific literature. They used cutting-edge techniques (whole-exome and RNA-Seq analysis) to sequence all the genes from the tumors and identified the mutations that are crucial for these tumors to grow and endure cancer treatment.

The study, conducted through international collaboration with research groups in Italy, Norway, South Korea, and the United States, revealed atypical genes and pathways that indicate NETc patients could benefit from precision medicine. Researchers say the findings better define the genetic landscape of NETc and suggest that a large subset of these highly aggressive malignancies might respond to existing targeted therapies.

The study was published April 15 in Proceedings of the National Academy of Sciences.

Our findings have important implications for the development of novel therapies since NETc are currently treated with common chemotherapy regimens used for patients with lung cancer. Our genetic data suggest that common regimens in combination with immunotherapies may represent a better choice."

Dr. Alessandro Santin, senior author, co-chief of the division of gynecologic oncology at YCC and a professor of obstetrics, gynecology & reproductive sciences at YSM

The study team sequenced tumor genes from 64 patients affected with NETc, including two patients with NETc tumors mixed with adenocarcinoma cells, cancer cells that form in glands that line certain organs. Using two fully sequenced patient-derived xenografts (PDX) -; in which patients' cancer cells were implanted in mice -; the researchers identified mutations that were crucial for the tumors to grow and survive treatment. The team also studied genes that were not mutated but were amplified in the tumors to give them a growth advantage over normal tissues.

Stefania Bellone, first author of the study and associate research scientist in the Department of Obstetrics, Gynecology & Reproductive Sciences at YSM, said that the genetic sequencing of tumors with both adenocarcinoma and neuroendocrine elements found for the first time that the neuroendocrine part of the tumor comes from the same type of cell that leads to the adenocarcinoma, meaning they each have similar genetic mutations typical of cancer.

The findings also showed many genes had repeated mutations and some had higher levels of certain genetic changes than others. Tumors with a higher number of mutations are potentially more sensitive to immunotherapy.

Corresponding author Joseph Schlessinger, the William H. Prusoff Professor of Pharmacology at YSM, said that creating two PDX models, each with their own mutation profile, allowed testing of each to determine if they could predict drug responses in living organisms. The approach holds promise for tailoring cancer treatments to individual patients, he said.

Source:
Journal reference:

Bellone, S., et al. (2024) Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix. PNAS. doi.org/10.1073/pnas.2321898121.

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