News on the fightfront for ovary cancer. Two new discoveries led by Cedars-Sinai Cancer investigators help improve the understanding of what drives the development of ovarian cancer and why some women’s tumors do not respond to therapy. The first study, published today in the Journal of the National Cancer Institute, identified four new regions of the human genome that harbor genetic variants or mutations that put women at an increased risk of developing epithelial ovarian cancer, the most common type of ovarian cancer. The first study, now appearing in the Journal of the National Cancer Institute, identified four new regions of the human genome that harbor genetic variants or mutations that put women at an increased risk of developing epithelial ovarian cancer, the most common type of ovarian cancer. To pinpoint the mutations, the team of investigators used new methods to analyze the structural variation of the genome. While most research focuses on analyzing the change in the sequence of the gene, the team looked at the number of copies of the gene an individual has, known as a copy number variant.
The researchers collaborated with scientists at the University of Cambridge to specifically look at deletions and duplications in 13,000 women with ovarian cancer and compared them to 17,000 women without ovarian cancer from the Ovarian Cancer Association Consortium to identify copy number variants that were associated with ovarian cancer risk. They found significant deletions and duplications in the BRCA1 gene, BRCA2 gene, and RAD51C gene, all of which are known to harbor changes in a patient’s DNA sequence that increase risk for ovarian cancer. Also found: four new genes that have not been previously linked to an increased risk for ovarian cancer. The second study, published in the Journal of Experimental Clinical Cancer Research, gives investigators a deeper understanding as to how ovarian tumors develop resistance to chemotherapy, which occurs in about 80% of high-grade serous ovarian cancer patients. Previously, researchers believed that ovarian tumors evolve after they are exposed to chemotherapy, and that they change their gene expression to adapt and survive through the treatment.
However, using whole genome sequencing, they found for the first time that this is not the case. Instead, it seems more likely that most high-grade serous ovarian tumors have the capacity to survive chemotherapy from a very early stage. The mechanism beneath this phenomeno is to be addressed to genome methylation patterns. Scientists identified significant differences in the burden of differentially methylated regions in BRCA1/2-positive cancers compared to non-BRCA1/2 carriers. In addition, there were overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival in the formers. From theses infrmations, scientists concluded that methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment. In other words, the chemodrug pressure would not be the main responsible for the tumoral evolution in terms of cellular response and possibly in the immunological response. But it could just be restricted to the ovary cancer.
Differently from sthe seouus type, mucinous ovarian cancer is a rare type of ovarian cancer. It actually has more in common with gastrointestinal cancers, and can be hard to diagnose and hard to treat once it has spread beyond the ovaries. A new research on this type of cancer could help oncologists recommend the best treatment for women who are diagnosed early with the condition. Guidelines on how to treat women with early-stage mucinous ovarian cancer, have differed around the world due to limited data on infiltrative patterns of invasion associated with survival rates. For example, in some parts of the world, an infiltrative pattern was acknowledged as an important feature and determined what treatment those women receive. Whereas in others, all patients are recommended for the same pathway of treatment. With this large study scientists hope that treatment guidelines can be aligned to a personalized consensus. By looking down a microscope for two different patterns of invasion, oncologists can better predict which patients may have better or worse prognoses and can target treatment accordingly.
Observing which of the two types of invasion patterns that the cancer cells form could help specialists decide on treatment strategies. The two patterns are defined by the way the cancer cells organize themselves when viewed under a microscope. The infiltrative pattern of invasion associated with poorer health outcomes shows cancer cells spreading in an uneven, haphazard way through the ovarian tissue. The other pattern is known as expansile, where cells expand through tissue in a more orderly manner, and is associated with better prognoses. Up until now, other studies had suggested that the infiltrative pattern of invasion was associated with poorer patient outcomes, but no study had large enough numbers of patients with early-stage cancer to reach statistical significance. But the current study, that involved more than 100 researchers in Australia, Europe, Asia and United States, was able to test this hypothesis in much larger numbers by examining the tissue of 604 patients. The researchers also looked for the expression of 19 genes including THBS2 and TAGLN, in addition to the patterns of invasion.
The women with higher expression of these two genes in their tumors, had poorer overall survival. This did let scientists think that these genes could help explain some of the biology potentially behind this type of cancer and wonder if knowledge of expression of these genes could assist in developing new targeted drugs.
- A cura del Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Dott. Gianfrancesco Cormaci
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