Tracking the clonal origin of lethal prostate cancer

Abstract

Recent controversies surrounding prostate cancer overtreatment emphasize the critical need to delineate the molecular features associated with progression to lethal metastatic disease. Here, we have used whole-genome sequencing and molecular pathological analyses to characterize the lethal cell clone in a patient who died of prostate cancer. We tracked the evolution of the lethal cell clone from the primary cancer to metastases through samples collected during disease progression and at the time of death. Surprisingly, these analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, and not from the bulk, higher-grade primary cancer or from a lymph node metastasis resected at prostatectomy. Despite being limited to one case, these findings highlight the potential importance of developing and implementing molecular prognostic and predictive markers, such as alterations of tumor suppressor proteins PTEN or p53, to augment current pathological evaluation and delineate clonal heterogeneity. Furthermore, this case illustrates the potential need in precision medicine to longitudinally sample metastatic lesions to capture the evolving constellation of alterations during progression. Similar comprehensive studies of additional prostate cancer cases are warranted to understand the extent to which these issues may challenge prostate cancer clinical management.

Application of a Clinical Whole-Transcriptome Assay for Staging and Prognosis of Prostate Cancer Diagnosed in Needle Core Biopsy Specimens

“…The unpredictability of disease progression is further affected by the genetic heterogeneity and multiclonality of tumors that can appear histologically identical or, surprisingly, even lower grade. 6,7 All of these challenges highlight the need for more sensitive and robust genomic-based risk stratification methods that are applicable to prostate biopsy specimens so that men can more confidently choose a proper cancer management strategy. The small amount of tumor usually present in FFPE tissue specimens poses a barrier that is particularly difficult to overcome in the analysis of tissue biomarkers.…”

Exome sequencing of contralateral breast cancer identifies metastatic disease

“…Exome sequencing has proved useful to identify somatic mutations and investigate the clonal relationship between primary tumors and various forms of recurrences in a wide range of cancers, including breast cancer [8][9][10][11]. Taken together, the results from exome sequencing in the field of oncology show a large genetic diversity between tumors from different patients, with only few positions in the genome being mutated in 10% or more of cancer cases.…”

Rewired Metabolism in Drug-resistant Leukemia Cells

“…Cancer is a clonal disease progressively producing new subclones displaying altered phenotypic and cytogenetic traits with selection for those that confer growth advantages under specific circumstances (1)(2)(3). Consequently, under therapeutic pressure, following the principles of natural selection, cancer cell populations that are most adaptive or resistant to treatment will be selected for, resulting in relapsing disease often associated with a worse prognosis (1,4,5).…”