Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer

Abstract

The extent of heterogeneity of driver gene mutations present in naturally occurring metastases is largely unknown, i.e. treatment-naïve metastatic disease. To address this issue, 60× whole genome sequencing of 26 metastases from 4 patients was carried out. We found that the identical driver gene mutations were present in every metastatic lesion of each patient studied. Passenger gene mutations not known or predicted to have functional consequences accounted for all intratumoral heterogeneity. Even with respect to these passenger gene mutations, the genetic similarity among the founding cells of metastases was markedly higher than that expected for any two cells randomly taken from a normal tissue. The uniformity of driver gene mutations among metastases in the same patient has critical, encouraging implications for the success of future targeted therapies in advanced stage disease.

The Heterogeneity of Prostate Cancer: A Practical Approach

“…While the very complex clonal heterogeneity in patients with metastatic disease [72] is under investigation, some studies show that analysis of a single metastasis could be enough to assess major oncogenic driver events because the genomic diversity between metastases is limited [37]. This fact has received confirmation from the evidence in studies on other types of tumors [87]. …”

Tumor Heterogeneity in Pancreatic Adenocarcinoma

“…Probably because of a differential expansion rate, subclones a few centimeters away from each other may be closer genetically than directly adjacent subclones. This could be viewed as a major obstacle when searching for alterations predictive of drug efficacy, yet it has been shown that all of the major tumor driver alterations are present in all subclones [47]. The biological significance of the additional alterations specific to subclones, that represent about 35% of the mutational burden, has yet to be proven to play a role in tumor progression.…”

Opportunities and Resistance to Signal-targeted Therapies in Pancreatic Cancer: What Can We Learn from Proteomic Studies?

“…It is involved in differences in the sensitivity of neoplastic cells to targeted therapies. In contrast, in a large scale genomic and genetic analysis, genetic alterations in metastasis sites were found to be maintained as compared to the primary site of tumorigenesis [21]. Thus, this study highlights the interest of a personalized therapeutic combination targeting all the subclonal features of metastases, using proteomics to guide the therapeutic choice.…”

“…One or more tumor subpopulations with different characteristics compared to the sensitive cells could emerge allowing them to survive and continue to proliferate in the presence of pharmacological inhibition, leading to a therapeutic failure [19 , 20]. The heterogeneity within tumor is thus a critical component of resistance mechanisms [21]. Technological progress and big data have led to a characterisation of pancreatic cancer's molecular identity (of mostly resected tumors) [22][23][24][25].…”