NEW YORK (GenomeWeb) – A new study in PLOS Medicine suggests serous ovarian cancer survival is typically worse for women who have more genetically distinct clonal subtypes present in their tumors.
Researchers from the UK did targeted tagged-amplicon sequencing (TAm-seq), whole-genome sequencing, and/or array-based copy number profiling on multiple tumor samples apiece from 14 women with high-grade serous ovarian cancer who were treated with platinum-based chemotherapy.
From phylogenetic patterns in samples collected over time and from different parts of the same tumor, they got a look at the intra-tumor heterogeneity characterizing each case. As it turned out, higher-than-usual clonal heterogeneity in the tumor typically coincided with shorter progression-free survival and overall survival times.
And for at least two women with cancer recurrence, the team pegged the relapse to the resurgence of cell sub-populations present from early stages of the disease, highlighting the potential for minor clones to expand after treatment when diversity in the tumor is high.
Such research "helps make sense of the genetic chaos inside tumors," the study's co-senior author James Brenton said.
"It's another step closer to cracking the code on cancer biology so that we can understand sooner how patients will respond to treatment — and how to develop better drugs for this hard-to-treat cancer in the future," continued Brenton, an oncology researcher at the University of Cambridge.
Past research has uncovered a role for expansion by treatment-resistant clones in blood cancers, the team noted. But while intra-tumor heterogeneity has been observed in solid tumors, its role in patient outcomes has been less well studied.
Brenton and his colleagues focused on 18 women with high-grade serous ovarian cancer, collecting 177 tumor samples, including metastases, over a median of 31 months. Following quality control steps, the team was left with information on three or more tumors samples for 14 of the patients.
Along with copy number profiling discerned from Affymetrix array testing on the tumors, the team assessed mutation patterns in seven suspicious genes using TAm-seq.
Through whole-genome sequencing on samples from half a dozen patients, the researchers also got a more extensive look at recurrent somatic mutations in the high-grade serous ovarian tumors.
As in prior genomic studies of high-grade serous ovarian cancer, they noted, the tumors often contained recurrent somatic mutations affecting the tumor suppressor gene TP53, though copy number aberrations tended to vary from one individual to the next.
By analyzing alterations in samples taken at different metastatic sites and stages of treatment in the same individual using an analytical method known as MEDICC, the study's authors got a peek at the clonal heterogeneity present in each case.
The analysis revealed differences in tumor diversity from on individual to the next, they reported.
Those with high levels of clonal expansion in their tumors had average survival times of less than two years compared to the almost 43-month average survival time detected in individuals with lower levels of clonal expansion in their tumors.
The relationship seems to reflect the availability of treatment-resistant sub-clones that can take over when other tumor cell populations succumb to chemotherapy, the team noted, consistent with the patterns identified in tumors from two of the relapsed patients.
Because sub-clones present early on can potentially expand after treatment, the study's authors argued that "quantitative measures of intra-tumor heterogeneity may have predictive value for survival after chemotherapy in [high-grade serous ovarian cancer]."