In the United States, lung cancer is the most common form of cancer and is responsible for more deaths than any other type of cancer among both men and women. Small cell lung cancer (SCLC) accounts for only 15% of all lung cancers, but it is the most aggressive form. SCLC patients rarely survive more than a few months without treatment. The lack of early symptoms, or the presentation of symptoms that are easily mistaken for other conditions, contribute to the poor prognosis. Because patients with SCLC often present with disseminated disease, the current standard of care for those who have clinical or pathological evidence of lymph node involvement have focused on systemic therapy consisting of several cycles of a combination of platinum-based chemotherapy plus a DNA topoisomerase inhibitor, along with concurrent thoracic radiotherapy. Some but not all patients are responsive to these agents, as judged by improved survival. A blood-based marker(s) that predicted response to these treatments would be helpful to inform appropriate treatment for SCLC patients. Scientists in Dr. Chu Chen’s laboratory in the Public Health Sciences Division at Fred Hutch recently published a paper in Clinical Cancer Research that reported on variants of a gene that may contribute to drug resistance and their association with survival of SCLC patients.
Topoisomerases are enzymes that cut DNA strands to allow DNA unwinding that is necessary for successful DNA replication and gene expression. The essential function of these enzymes is underscored by the fact that when chemically inhibited, cellular division is impaired and cells die. Thus, inhibitors of topoisomerases, sometimes termed topoisomerase poisons, are commonly used chemotherapeutic agents to induce cancer cell death. Another enzyme, tyrosyl-DNA phosphodiesterase (TDP1), cleans up topoisomerase-induced damage by removing transient links between topoisomerases and DNA allowing for repair of the DNA strand breaks. TDP1, as described by Chen, “is hypothesized to be responsible for drug resistance to DNA topoisomerase inhibitors.” Because TDP1 is implicated in reduced cancer treatment effectiveness, the Chen group was interested in investigating whether genetic variants of TDP1 may be related to patient survival. Says Chen, “There are very few studies on TDP1 polymorphisms and, to the best of our knowledge, our study is the first to investigate TDP1 polymorphisms in relation to lung cancer survival.”
The authors analyzed genetic variants, called single nucleotide polymorphisms (SNPs), of the TDP1 gene in nearly 900 SCLC patients. A strength of the study lies in this large number of patients, as Chen explains, “Because there are few studies that have collected treatment and survival data on patients with SCLC and the number of SCLC cases in each of the studies that have done so is relatively small, the present study is only possible by pooling the data from several collaborating studies in the International Lung Cancer Consortium. Studies that contributed to this effort include studies that were conducted in the US, Canada, Spain, Italy, United Kingdom and Japan.” The authors focused their efforts specifically on two SNPs, rs942190 and rs2401863, and their associations with lung cancer survival at 36 months post-diagnosis.
Image by Maggie Burhans
The aggressive nature of SCLC was evident in this study, as approximately 90% of patients had died by 36 months after diagnosis. Survival analyses were then conducted for each of the two SNPs. Poorer survival was associated with carrying two copies of the rs942190 minor allele as compared to carrying only one copy of the minor allele or two copies of the major allele. The authors found that the patients homozygous for the minor allele had a 36% increased risk of death by 36 months post-diagnosis (see figure). In contrast, the minor allele of the rs2401863 SNP tended to be associated with better overall survival. Follow-up subgroup analyses revealed differential effects of this minor allele on survival by race; homozygosity for the less common allele tended to be associated with poorer survival among Asian patients but better survival among Caucasian patients.
Using the Genotype-Tissue Expression Project database, the authors also investigated differences in TDP1 expression for each of the SNPs. They found that in lung tissue of non-diseased individuals, TDP1 expression is significantly higher in individuals that carry two copies, as compared to individuals with one or no copies, of the rs942190 minor allele. Elevated expression of TDP1 may be a possible explanation for resistance to topoisomerase inhibitors and poorer survival of SCLC patients homozygous for the minor allele.
Dr. Chen indicated that the next steps to follow-up these findings should include “the conduct of prospective studies to gauge whether TDP1 rs942190 genotype would be useful as a prognostic marker for SCLC patients or a predictive marker for treatment response to DNA topoisomerase inhibitors, and to conduct in vitro and in vivo studies to evaluate the function of TDP1 rs942190 genotypes to gain insight into the biological basis of, or the lack of, our observation.”
Also contributing to this project from Fred Hutch were Drs. Pawadee Lohavanichbutr, Gary Goodman, and Noel Weiss.
Lohavanichbutr P,Sakoda LC,Amos CI,Arnold SM,Christiani DC,Davies MPA,Field JK,Haura EB,Hung RJ,Kohno T,Landi MT,Liu G,Liu Y,Marcus MW,O'Kane GM,Schabath MB,Shiraishi K,Slone SA,Tardon A,Yang P,Yoshida K,Zhang R,Zong X,Goodman GG,Weiss NS,Chen C. 2017. Common TDP1 polymorphisms in relation to survival among small cell lung cancer patients: a multicenter study from the International Lung Cancer Consortium. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-17-1401.
Funding for this study was provided by the National Institutes of Health.