A patient-driven clinicogenomic partnership for metastatic prostate cancer

Crowdis, Jett; Balch, Sara; Sterlin, Lauren; Thomas, Beena; Camp, Sabrina Y.; Dunphy, Michael; Anastasio, Elana; Shah, Shahrayz; Damon, Alyssa L.; Ramos, Rafael; Sosa, Delia; Small, Ilan K.; Tomson, Brett N.; Nguyen, Colleen; McGillicuddy, Mary; Chastain, Parker; He, Meng Xiao; Cheung, Alexander; Wankowicz, Stephanie A.; Tewari, Alok K.; Kim, Dewey; AlDubayan, Saud H.; Dowdye, Ayanah; Zola, Benjamin; Nowak, Joel; Manarite, Jan; Gunn, Idola Henry; Olson, Bryce; Lander, Eric S.; Wagle, Nikhil; Allen, Eliezer M. Van

doi:10.1016/j.xgen.2022.100169

Cited by 6 publications

(4 citation statements)

References 75 publications

(91 reference statements)

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“…For survival data, all prostate cancer studies within the CBioPortal database were selected and queried specifically for HOXA9 genomic amplification or gain using default settings (32). Analysis of indicated hormone sensitive prostate cancer studies (33,(58)(59)(60) including the TCGA firehose legacy (https://www.cancer.gov/tcga), and castration resistance (28,(61)(62)(63) prostate cancer datasets were also queried specifically for HOXA9 amplification or gain. For transcriptomic data from the SU2C/PCF Dream Team (28), FPKM PolyA mRNA data was used for analysis.…”

Section: Methodsmentioning

confidence: 99%

A genome wide CRISPR screen reveals that HOXA9 promotes Enzalutamide resistance in prostate cancer

Roes,

Dick

2023

Preprint

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Androgen receptor inhibitors are commonly used for prostate cancer treatment, but acquired resistance is a significant problem. Co-deletion of RB and p53 is common in castration resistant prostate cancers, however they are difficult to target pharmacologically. To comprehensively identify gene loss events that contribute to enzalutamide response, we performed a genome-wide CRISPR knockout screen in LNCaP prostate cancer cells. This revealed novel genes implicated in resistance that are largely unstudied. Gene loss events that confer enzalutamide sensitivity are enriched for GSEA categories related to stem cell and epigenetic regulation. We investigated the myeloid lineage stem cell factor HOXA9 as a candidate gene whose loss promotes sensitivity to enzalutamide. Cancer genomic data reveals that HOXA9 overexpression correlates with poor prognosis and characteristics of advanced prostate cancer. In cell culture, HOXA9 depletion sensitizes cells to enzalutamide, whereas overexpression drives enzalutamide resistance. Combination of the HOXA9 inhibitor DB818 with enzalutamide demonstrates synergy. This demonstrates the utility of our CRISPR screen data in discovering new approaches for treating enzalutamide resistant prostate cancer.

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Section: Methodsmentioning

confidence: 99%

A genome wide CRISPR screen reveals that HOXA9 promotes Enzalutamide resistance in prostate cancer

Roes,

Dick

2023

Preprint

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“…Kataegic SNVs likely originated simultaneously from exposed single strand DNAs (ssDNA) by APOBEC3A and APOBEC3B cytidine deaminases, as evidenced by yeast experiments 18 and through association with APOBEC genes expression 5 . Being less common in PCa compared to other cancer types 5 , kataegis has received little to no focus 19,20,21 . In turn, kataegis remains unexplored with respect to ancestrally derived tumour genome and clinical disparities, speci cally aggressive disease in African men.…”

Section: Introductionmentioning

confidence: 99%

Kataegis associated mutational processes linked to adverse prostate cancer presentation in African men

Hayes,

Jiang,

Tapinos

et al. 2024

Preprint

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Kataegis, the focal hypermutation of single base substitutions (SBS) in tumour genomes, has received little attention with respect to prostate cancer (PCa) associated molecular and clinical features. Most notably, data is lacking with regards to this tumour evolutionary phenomenon and PCa racial disparities, with African men disproportionately impacted. Here through comparison between African (n = 109) and non-African (n = 79) whole genome sequenced treatment naïve primary tumours, using a single analytical workflow we assessed for shared and unique features of kataegis. Linking kataegis to aggressive presentation, structural variant burden and copy number loss, we attributed APOBEC3 activity through higher rates of SBS2 to high-risk African tumours. While kataegis positive African patients presented with elevated prostate specific antigen levels, their tumours showed evolutionary unique trajectories marked by increased subclonal and structural variant-independent kataegis. The potential to exacerbate tumour heterogeneity emphases the significance of continued exploration of biological behaviours and environmental exposures for African patients.

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“…However, most of these studies have focused on primary breast cancers, are often conducted by a single institution, and are limited to studying patient cohorts that receive cancer care at major cancer centers 6,7,[10][11][12][13][14][15] . This traditional approach of conducting research has potentially resulted in a skewed characterization of metastatic breast cancer (MBC) that does not capture the full range and diversity of cancer patients, as has been observed in other cancers [16][17][18] , and an unmet need to correct this.…”

Section: Introductionmentioning

confidence: 99%

“…Harnessing the power of social media and online communities that allow people to connect irrespective of geography, we engaged with members of the metastatic breast cancer community to listen to their experiences and understand their specific needs and perspectives. These initial relationships established with patients, advocates, and advocacy groups led to extensive discussions to frame and shape this new model of patient-partnered research, which has ultimately proven to be a successful research modality that has led to scientific discoveries with clinical impact in multiple cancer types 18,19 .…”

Section: Introductionmentioning

confidence: 99%

The Metastatic Breast Cancer Project: leveraging patient-partnered research to expand the clinical and genomic landscape of metastatic breast cancer and accelerate discoveries

Jain

Zañudo

McGillicuddy

et al. 2023

Preprint

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Capturing the full complexity of the clinical experiences of metastatic breast cancer (MBC) patients treated in a variety of settings is needed to better understand this disease and develop new treatment modalities. Yet, challenges exist to establish and share a large MBC dataset that integrates genomic, clinical, and patient-reported data as it requires collecting information and samples from many geographically dispersed patients and institutions. We explored whether a patient-partnered research approach that uses online engagement could enable patients living across the United States and Canada to accelerate cancer research by sharing their samples, clinical information, and experiences. In collaboration with patients and patient advocates, the Metastatic Breast Cancer Project (MBCproject; www.mbcproject.org) was developed and launched in October 2015. As of March 2020, 3,246 MBC patients who received treatment at ~1,700 institutions had consented for the MBCproject, providing patient-reported information via surveys, as well as access to medical records and biological samples. Through the collection and analysis of tumor and germline samples, medical records, and patient-reported data, the MBCproject generates and publicly releases clinically-annotated genomic data on primary and metastatic tumor specimens on a recurring basis. Herein we describe the MBCproject cohort in detail and describe the clinico-genomic landscape of the MBCproject dataset. The complete dataset consists of whole exome sequencing (WES) for 379 tumors with matching germline from 301 patients, WES on germline samples from 377 patients, and transcriptome sequencing (RNA-seq) for 200 tumors from 141 patients, with clinical data from medical records and patient-reported information. A comparison of various clinical fields (diagnostic dates, tumor histology, tumor sites, treatments received) obtained from patient-reported data and the abstracted from medical records found a high degree of concordance, with multiple fields having over 90% concordance. Analysis of the somatic alterations in the 249 tumors taken after metastatic diagnosis found a significant enrichment of mutations in the cancer genesTP53,PIK3CA,CDH1,PTEN,AKT1,NF1, andESR1, among others. Tumor evolutionary analysis of 14 patients with 3 or more samples identified oncogenic mutations inESR1,NF1, andTP53, genes associated with MBC and/or resistance to endocrine therapy. Analysis of germline samples identified pathogenic variants in the cancer-associated genesBRCA1,BRCA2,ATM, andPALB2. Comparing the frequency of pathogenic variants in patients diagnosed before/at or after the age of 40 years old, we found that the presence of these variants inBRCA1orBRCA2was enriched in the younger group compared to the older group (9.2% vs 2.5%, p=0.0089; two-sided Fisher exact test). Transcriptome sequencing identified putatively oncogenic in-frame fusions in cancer genes such asFANCD2,FGFR3,ESR1,BRAFandNCOR1. Analysis of tumor's intrinsic molecular subtype (research-based PAM50) found a depletion of the Luminal A subtype in MBCproject compared to The Cancer Genome Atlas, and a switch in molecular subtype in 15 out of 35 patients with 2 or more samples. A case study of a patient with sequencing data from 4 tumor biopsies obtained during the course of their metastatic disease is presented. An integrated analysis of the clinical and multi-omic data from this patient identified distinct drivers of resistance to endocrine therapy in each of these tumors. The MBCproject clinico-genomic dataset is one of the largest available MBC patient cohorts This integrated dataset is poised for studying several understudied clinical cohorts (young women with breast cancer,de novoMBC), rare disease subtypes (e.g. lobular, metaplastic, extraordinary responders), biomarkers of response/resistance (e.g. CDK4/6 inhibitors), and real world patterns, among others, and will serve as an invaluable resource to accelerate discoveries.

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A patient-driven clinicogenomic partnership for metastatic prostate cancer

Cited by 6 publications

References 75 publications

A genome wide CRISPR screen reveals that HOXA9 promotes Enzalutamide resistance in prostate cancer

A genome wide CRISPR screen reveals that HOXA9 promotes Enzalutamide resistance in prostate cancer

Kataegis associated mutational processes linked to adverse prostate cancer presentation in African men

The Metastatic Breast Cancer Project: leveraging patient-partnered research to expand the clinical and genomic landscape of metastatic breast cancer and accelerate discoveries

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