Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal ...adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.
We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated:
, and
HRm status was grouped as: (i) germline versus somatic; (ii) core (
and
versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden.
Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median 95% confidence interval (CI) follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum HR, 0.44 (95% CI: 0.29-0.67);
< 0.01, but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum.
Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.
The fundamental metabolic decision of a cell, the balance between respiration and fermentation, rests in part on expression of the mitochondrial genome (mtDNA) and coordination with expression of the ...nuclear genome (nuDNA). Previously we described mtDNA copy number depletion across many solid tumor types (Reznik et al., 2016). Here, we use orthogonal RNA-sequencing data to quantify mtDNA expression (mtRNA), and report analogously lower expression of mtRNA in tumors (relative to normal tissue) across a majority of cancer types. Several cancers exhibit a trio of mutually consistent evidence suggesting a drop in respiratory activity: depletion of mtDNA copy number, decreases in mtRNA levels, and decreases in expression of nuDNA-encoded respiratory proteins. Intriguingly, a minority of cancer types exhibit a drop in mtDNA expression but an increase in nuDNA expression of respiratory proteins, with unknown implications for respiratory activity. Our results indicate suppression of respiratory gene expression across many cancer types.
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, highly aggressive form of ovarian cancer primarily diagnosed in young women. We identified inactivating biallelic SMARCA4 ...mutations in 100% of the 12 SCCOHT tumors examined. Protein studies confirmed loss of SMARCA4 expression, suggesting a key role for the SWI/SNF chromatin-remodeling complex in SCCOHT.
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Tumor genetic testing is standard of care for patients with advanced lung adenocarcinoma, but the fraction of patients who derive clinical benefit remains undefined. Here, we report the experience of ...860 patients with metastatic lung adenocarcinoma analyzed prospectively for mutations in >300 cancer-associated genes. Potentially actionable genetic events were stratified into one of four levels based upon published clinical or laboratory evidence that the mutation in question confers increased sensitivity to standard or investigational therapies. Overall, 37.1% (319/860) of patients received a matched therapy guided by their tumor molecular profile. Excluding alterations associated with standard-of-care therapy, 14.4% (69/478) received matched therapy, with a clinical benefit of 52%. Use of matched therapy was strongly influenced by the level of preexistent clinical evidence that the mutation identified predicts for drug response. Analysis of genes mutated significantly more often in tumors without known actionable mutations nominated
and
as possible targetable mitogenic drivers.
An increasing number of therapies that target molecular alterations required for tumor maintenance and progression have demonstrated clinical activity in patients with lung adenocarcinoma. The data reported here suggest that broader, early testing for molecular alterations that have not yet been recognized as standard-of-care predictive biomarkers of drug response could accelerate the development of targeted agents for rare mutational events and could result in improved clinical outcomes.
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The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear.
In patients with metastatic castration-sensitive prostate cancer at a ...tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high volume (≥4 bone metastases or visceral metastases) versus low volume.
Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease, 275 (65%) had
metastatic disease, and 149 (35%) had metastatic recurrence of nonmetastatic disease. Rates of castration resistance adjusted hazard ratio, 1.84; 95% confidence interval (CI), 1.40-2.41 and death (adjusted hazard ratio, 3.71; 95% CI, 2.28-6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifier pathways were the highest-ranking pathways enriched in high-volume disease.
metastatic disease differed from metastatic recurrences in the prevalence of
alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in
(inverse), and
, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to
(inverse), WNT (inverse), and cell-cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors.
This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection.
Cancer evolves through the emergence and selection of molecular alterations. Cancer genome profiling has revealed that specific events are more or less likely to be co-selected, suggesting that the ...selection of one event depends on the others. However, the nature of these evolutionary dependencies and their impact remain unclear. Here, we designed SELECT, an algorithmic approach to systematically identify evolutionary dependencies from alteration patterns. By analyzing 6,456 genomes from multiple tumor types, we constructed a map of oncogenic dependencies associated with cellular pathways, transcriptional readouts, and therapeutic response. Finally, modeling of cancer evolution shows that alteration dependencies emerge only under conditional selection. These results provide a framework for the design of strategies to predict cancer progression and therapeutic response.
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•SELECT identifies cancer evolutionary dependencies from alteration occurrences•Pan-cancer dependencies reflect tissue-independent functional interactions•Pan-cancer dependencies influence response to therapy•Conditional selection is required for the emergence of evolutionary dependencies
Using an algorithmic approach that they design, Mina et al. construct a pan-cancer map of oncogenic dependencies and find several co-dependent alterations that modify drug response. These results provide a framework to improve cancer therapy by anticipating drug resistance and proposing alternative strategies.
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The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability-high (MSI-H) or mismatch ...repair-deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown.
To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population.
In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018.
Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases.
Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean SD age, 65.6 9.3 years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome-associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti-PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total 45.5%) were still on therapy for as long as 89 weeks.
The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti-PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance.
Glioblastoma multiforme (GBM) is the most common and aggressive type of brain tumor in humans and the first cancer with comprehensive genomic profiles mapped by The Cancer Genome Atlas (TCGA) ...project. A central challenge in large-scale genome projects, such as the TCGA GBM project, is the ability to distinguish cancer-causing "driver" mutations from passively selected "passenger" mutations.
In contrast to a purely frequency based approach to identifying driver mutations in cancer, we propose an automated network-based approach for identifying candidate oncogenic processes and driver genes. The approach is based on the hypothesis that cellular networks contain functional modules, and that tumors target specific modules critical to their growth. Key elements in the approach include combined analysis of sequence mutations and DNA copy number alterations; use of a unified molecular interaction network consisting of both protein-protein interactions and signaling pathways; and identification and statistical assessment of network modules, i.e. cohesive groups of genes of interest with a higher density of interactions within groups than between groups.
We confirm and extend the observation that GBM alterations tend to occur within specific functional modules, in spite of considerable patient-to-patient variation, and that two of the largest modules involve signaling via p53, Rb, PI3K and receptor protein kinases. We also identify new candidate drivers in GBM, including AGAP2/CENTG1, a putative oncogene and an activator of the PI3K pathway; and, three additional significantly altered modules, including one involved in microtubule organization. To facilitate the application of our network-based approach to additional cancer types, we make the method freely available as part of a software tool called NetBox.
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Primary prostate cancer is the most common malignancy in men but has highly variable outcomes, highlighting the need for biomarkers to determine which patients can be managed conservatively. Few ...large prostate oncogenome resources currently exist that combine the molecular and clinical outcome data necessary to discover prognostic biomarkers. Previously, we found an association between relapse and the pattern of DNA copy number alteration (CNA) in 168 primary tumors, raising the possibility of CNA as a prognostic biomarker. Here we examine this question by profiling an additional 104 primary prostate cancers and updating the initial 168 patient cohort with long-term clinical outcome. We find that CNA burden across the genome, defined as the percentage of the tumor genome affected by CNA, was associated with biochemical recurrence and metastasis after surgery in these two cohorts, independent of the prostate-specific antigen biomarker or Gleason grade, a major existing histopathological prognostic variable in prostate cancer. Moreover, CNA burden was associated with biochemical recurrence in intermediate-risk Gleason 7 prostate cancers, independent of prostate-specific antigen or nomogram score. We further demonstrate that CNA burden can be measured in diagnostic needle biopsies using low-input whole-genome sequencing, setting the stage for studies of prognostic impact in conservatively treated cohorts.
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