Local genetic mutations can serve as biomarkers for a wide range of cancers

Source: Brianna Monroe/Northwestern University

A group of investigators at Northwestern Medicine has successfully localized the novel molecular mechanisms behind a genetic mutation found in a wide range of cancers, which may serve as a biomarker for improving stratification and patient treatment, according to findings published in Proceedings of the National Academy of Sciences.

“It is very gratifying to be able to work on a molecular project for many years and link the findings to the clinical stratification of patients with cancer, especially bladder cancer in this case, and more to develop targeted therapies for the treatment of bladder cancer that can be used in other forms of cancer such as lung, colon and other solid tumors,” said Zibo Zhao, Ph.D., assistant who is professor of Biochemistry and Molecular Genetics and lead author of the study.

Ali Shilatifard, Ph.D., the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics, is the senior author of the study.

Mutations in the MLL4 gene, which belongs to a set of genes known as the Complex of Proteins Associated with Set1 (COMPASS) family, are found in patients with many types of cancer, including bladder cancer , colorectal cancer, esophageal cancer, endometrial cancer and acute. lymphoid leukemia, etc.






Source: Brianna Monroe/Northwestern University

In previous work from the Shilatifard laboratory, published in Journal of Clinical Investigationinvestigators discovered cancer cells with MLL4 mutations were more sensitive to purine synthesis inhibitors, which inhibited cancer cell growth, findings that further highlighted the potential of MLL4 as a therapeutic target.

In the current study, the investigators used CRISPR gene editing to determine the precise molecular mechanisms of cancer cell lines with MLL4 mutations. By using immunohistochemistry techniques in tissue samples from patients with bladder cancer, scientists found that MLL4 mutations localize in the cytoplasm of cancer cells.

The team then used a metabolic inhibitor called Lometrexol in a mouse model of bladder cancer, which significantly reduced the tumor stage in mice with MLL4 mutations, suggesting that MLL4 mutations may be functional. to stratify patients based on expected sensitivity to targeted therapies such as lometrexol.

“About one-third of patients with bladder cancer have MLL4 mutations,” Joshua Meeks, ’05 MD, ’03 Ph.D., ’06 ’11 GME, Edward M. Schaeffer, MD, Ph .D. Professor of Urology, associate professor of Biochemistry and Molecular Genetics, and a co-author of the study. “Lometrexol works like methotrexate, which is part of our chemotherapy regimen for bladder cancer. This study may explain why the drug is effective in almost half of the patients.”

The study suggests that cytoplasmic MLL4 mutation may serve as a biomarker for improving patient stratification and treatment outcomes, according to the authors.

“Cytoplasmic change in MLL4 can be a simple but powerful biomarker to better predict the response to methotrexate regimens. Unfortunately, there is a shortage of methotrexate so it is good to continue lometrexol in this situation. science at our hospital,” Meeks said.

The findings may also inform the development of new targeted therapies that restore MLL4 function in various cancers and diseases.

“The paper represents a way that you can stratify patients with bladder cancer based on the presence of MLL4 in the cytoplasm, and those who have MLL4 in the cytoplasm may be good candidates for this metabolic therapy that we know,” said Shilatifard, who is also director of the Simpson Querrey Institute for Epigenetics and leader of the Cancer Epigenetics & Nuclear Dynamics Program at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center.

More information:
Zibo Zhao et al, Somatic mutations in MLL4/COMPASS induce cytoplasmic localization providing molecular insights into cancer prognosis and treatment, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2310063120

Provided by Northwestern University

Citation: Localized genetic mutations may serve as biomarkers for a wide range of cancers (2023, December 21) retrieved 21 December 2023 from https://medicalxpress.com/news/2023-12-localized-genetic-mutations-biomarker-wide .html

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