Overexpression of Genes May Predict Positive Response to Treatment

Abnormal CEN and KT function causes CIN through chromosome missegregation, leading to aneuploidy, rearrangements, and micronucleus formation.

In order to test the hypothesis that dysregulation of CEN/KT genes caused chromosomal abnormalities that contributed to tumor formation and could be used as a biomarker for predicting patient prognosis and response to therapy, investigators at the Lawrence Berkeley National Laboratory (Berkeley, CA, USA) focused on genes regulating the function of centromeres and kinetochores – the essential sites on chromosomes for spindle fiber attachment during cell division.

The investigators examined several public cancer databases that provided information on DNA mutations and chromosome rearrangements, the presence and levels of specific proteins, the stage of tumor growth at the time the patient was diagnosed, treatments given, and patient status in the years following diagnosis and treatment.

This information combined with the mapping of 31 genes involved in regulating centromere and kinetochore function enabled the investigators to generate a CEN/KT gene expression score (CES) based on patient outcomes either with or without treatments.

In a paper published in the August 31, 2016, online edition of the journal Nature Communications, the investigators reported that overexpression of 14 CEN/KT genes was observed consistently in a wide spectrum of cancer types and correlated with the level of genomic instability in diverse tumors and with adverse tumor properties in a cancer-type-specific manner. High CES values correlated with increased levels of genomic instability and several specific adverse tumor properties, and indicated poor patient survival for breast and lung cancers, especially early-stage tumors.

In contrast, the high degree of chromosomal instability rendered cancer cells more vulnerable to the effects of chemotherapy or radiation therapy, and the CES signature could be used to predict whether such therapy was likely to be effective.

“The overexpression of a specific centromere protein resulted in extra spindle attachment sites on the chromosomes,” said senior author Dr. Gary Karpen, senior researcher in the division of biological systems and engineering at the Lawrence Berkeley National Laboratory. “This essentially makes new centromeres functional at more than one place on the chromosome, and this is a huge problem because the spindle tries to connect to all the sites. If you have two 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.”

“The history of cancer treatment is filled with overreaction,” said Dr. Karpen. “It is part of the ethics of cancer treatment to err on the side of over treatment, 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.”

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Lawrence Berkeley National Laboratory