Biomarker May Help Determine Value of Certain Cancer Treatments

An overexpression of 14 genes that regulate genome integrity were linked to prognosis and treatment response in cancer patients, according to a study in Nature Communications.

The study’s findings could be used to help develop a biomarker for the early stages of tumor development, and to predict patient response to cancer treatments.

“The history of cancer treatment is filled with overreaction,” said principal study investigator Gary Karpen. “It is part of the ethics of cancer treatment to err on the side of overtreatment, but these treatments have serious side effects associated with them. For some people, it may be causing more trouble than if the growth was left untreated.”

One hurdle is that physicians are only able to reliably determine whether patients will respond to chemotherapy or radiation therapy at an early stage.

“Even for early stage cancer patients, such as lung cancers, adjuvant chemotherapy and radiotherapy are routinely used in treatment, but overtreatment is a major challenge,” said lead study author Weiguo Zhang. “For certain types of early stage lung cancer patients, there are estimates that adjuvant chemotherapy improves 5-year survival only about 10%, on average, which is not great considering the collateral damage caused by this treatment.”

Based on results from early research by Karpen and his team, researchers focused genes that regulate the function of centromeres and kinetochores. During normal cell division, microtubule spindles grab onto the kinetochores, and pull the chromosome’s 2 chromatids apart.

Previously, the research team found that the overexpression of a specific centromere protein resulted in extra spindle attachment sites on the chromosomes of fruit flies.

“This essentially makes new centromeres functional at more than 1 place on the chromosome, and this is a huge problem because the spindle tries to connect to all the sites,” Karpen said. “If you have 2 or more of these sites on the chromosome, the spindles are pulling in too many directions, and you end up breaking the chromosome during cell division. So overexpression of these genes may be a major contributing factor to chromosomal instability, which is a hallmark of all cancers.”

Although chromosomal instability is believed to be a characteristic of cancer, the cause has been unclear. In an effort to identify the cause, researchers analyzed numerous public datasets from the National Center for Biotechnology Information, the Broad Institute, and other organizations, containing thousands of human clinical tumor samples from at least a dozen types of cancer.

The records from the database included information on the stage of tumor growth at the time of diagnosis, treatments, patient status following diagnosis and treatment, DNA mutations and chromosome rearrangements, and the presence and levels of specific proteins.

For the study, researchers screened 31 genes involved in regulating centromere and kinetochore function, in order to identify 14 that were consistently overexpressed in cancer tissue.

The extensive records allowed researchers to correlate the centromere and kinetochore gene expression score (CES) with patient outcomes, either with or without treatments.

“We were surprised to find such a strong correlation between CES and things like whether the patient survived 5 years later,” Karpen said. “Another finding — one that is counterintuitive – is that high expression of these centromere genes is also related to more effective chemotherapy and radiation therapy.”

Additionally, researchers theorized the degree of chromosomal instability might cause cancer cells to become more vulnerable to chemotherapy and radiation.

“In other words, there’s a threshold of genome instability,” Zhang said. “At low to medium-high levels, the cancer thrives. But at much higher levels, the cancer cells are more susceptible to the additional DNA damage caused by the treatment. This is a really key point.”

The study authors noted there was no link found between very high levels of genome instability, and the improvement of patient survival without adjuvant treatments. Furthermore, although there are several factors that need to be taken into consideration when choosing a treatment option, these findings could become an additional tool to help determine whether or not a patient should have a certain therapy

It could also help evaluate alternatives to the standard course of treatment.

“These findings are very exciting,” said study co-author Anshu Jain. “The biomarker score provides predictive and prognostic information separate from and independent of clinical and pathologic tumor characteristics that oncologists have available today and which often provide only limited clinical value.

“Future steps will include investigating the CES in prospective clinical studies for validation in carefully selected patient cohorts. By establishing the clinical significance of the CES, oncologists will have greater confidence in guiding cancer patients toward treatments with the greatest benefit.”