Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer

Abstract

We report the first combined analysis of whole-genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole-genome and transcriptome sequence was obtained from nine anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 yr before death. Transcriptome analysis revealed increased expression of androgen receptor (AR)-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only one of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today, given this knowledge, the use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merit further study. Our findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials.

Clinical relevance of androgen receptor alterations in prostate cancer

“…Enzalutamide and ARN509 (apalutamide) have agonist effects also on the H875Y, T878A and T878S mutations, all detected in CRPC patients ( 38 ), but acquired resistance to those drugs may primarily depend on increased expression of the glucocorticoid receptor and AR bypass ( 45 , 46 ) or the induction of constitutively active AR variants, as discussed below. The T878A , H875Y and the L702H mutations have been observed in CRPC patients progressing during abiraterone treatment and associated with either the increased progesterone levels obtained after CYP17 inhibition ( 25 , 47 , 48 , 49 ) or with the co-administration of exogenous glucocorticoids given to compensate for significantly reduced cortisol levels ( 26 , 50 , 51 , 52 ). The activating AR point mutations T877A, L702H and H875Y have been detected in cfDNA from patients with CRPC and shown to be associated with resistance to abiraterone and enzalutamide ( 25 , 26 , 42 , 49 ).…”

Genomic aberration based molecular signatures efficiently characterize homologous recombination deficiency in prostate cancer

“…It has been previously demonstrated that [28] that metastasis to metastasis spread of prostate tumor clones is common. This may explain the small heterogeneity seen in HRstatus of multiple metastases.…”

The ProBio Trial: Molecular Biomarkers for Advancing Personalized Treatment Decision in Patients with Metastatic Castration-Resistant Prostate Cancer

“…Biomarker driven clinical trials for mCRPC have been hampered by the difficulty of obtaining metastatic tissue (11). Also, profiling a single metastatic lesion is not capable of providing the full spectrum of the molecular heterogeneity that may exist within the patient (12,13). A liquid biopsy, either in the form of circulating tumour cells (CTCs) or tumour-derived cell-free DNA (circulating tumor DNA, ctDNA), is an attractive alternative (14,15).…”