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1.
Cell ; 186(9): 1985-2001.e19, 2023 04 27.
Article in English | MEDLINE | ID: mdl-37075754

ABSTRACT

Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer. Here, we describe KaryoCreate (karyotype CRISPR-engineered aneuploidy technology), a system that enables the generation of chromosome-specific aneuploidies by co-expression of an sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to mutant KNL1. We design unique and highly specific sgRNAs for 19 of the 24 chromosomes. Expression of these constructs leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny, with an average efficiency of 8% for gains and 12% for losses (up to 20%) validated across 10 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, frequent in gastrointestinal cancers, promotes resistance to TGF-ß, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe an innovative technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.


Subject(s)
Centromere , Genetic Techniques , Humans , Aneuploidy , Centromere/genetics , Chromosome Deletion , Neoplasms/genetics , Clustered Regularly Interspaced Short Palindromic Repeats
2.
Cell ; 168(4): 566-570, 2017 02 09.
Article in English | MEDLINE | ID: mdl-28187278

ABSTRACT

Study of the biology of tumors caused by germline mutations has led to recent paradigm-changing therapy and is driving precision prevention efforts, including immune oncology and early detection research. Here, we explore recent biologic advances that are redefining the spectrum of cancers linked to various hereditary predisposition syndromes and can be leveraged to improve personalized risk assessment and develop novel interventions to prevent or intercept cancer.


Subject(s)
Genetic Predisposition to Disease , Neoplasms/genetics , Neoplasms/prevention & control , Precision Medicine/methods , Animals , Germ-Line Mutation , Humans
3.
Nature ; 616(7957): 504-509, 2023 04.
Article in English | MEDLINE | ID: mdl-37046091

ABSTRACT

Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with several cancers of lymphocytic and epithelial origin1-3. EBV encodes EBNA1, which binds to a cluster of 20 copies of an 18-base-pair palindromic sequence in the EBV genome4-6. EBNA1 also associates with host chromosomes at non-sequence-specific sites7, thereby enabling viral persistence. Here we show that the sequence-specific DNA-binding domain of EBNA1 binds to a cluster of tandemly repeated copies of an EBV-like, 18-base-pair imperfect palindromic sequence encompassing a region of about 21 kilobases at human chromosome 11q23. In situ visualization of the repetitive EBNA1-binding site reveals aberrant structures on mitotic chromosomes characteristic of inherently fragile DNA. We demonstrate that increasing levels of EBNA1 binding trigger dose-dependent breakage at 11q23, producing a fusogenic centromere-containing fragment and an acentric distal fragment, with both mis-segregated into micronuclei in the next cell cycles. In cells latently infected with EBV, elevating EBNA1 abundance by as little as twofold was sufficient to trigger breakage at 11q23. Examination of whole-genome sequencing of EBV-associated nasopharyngeal carcinomas revealed that structural variants are highly enriched on chromosome 11. Presence of EBV is also shown to be associated with an enrichment of chromosome 11 rearrangements across 2,439 tumours from 38 cancer types. Our results identify a previously unappreciated link between EBV and genomic instability, wherein EBNA1-induced breakage at 11q23 triggers acquisition of structural variations in chromosome 11.


Subject(s)
Chromosome Breakage , DNA , Herpesvirus 4, Human , Viral Proteins , Humans , Binding Sites , DNA/chemistry , DNA/metabolism , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/metabolism , Herpesvirus 4, Human/pathogenicity , Viral Proteins/genetics , Viral Proteins/metabolism , DNA Breaks, Double-Stranded , Chromosomes, Human, Pair 11/chemistry , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 11/metabolism , Genomic Instability , Mitosis
4.
Nature ; 616(7958): 798-805, 2023 04.
Article in English | MEDLINE | ID: mdl-37046089

ABSTRACT

Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1-6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.


Subject(s)
Adenocarcinoma , Barrett Esophagus , Carcinogenesis , DNA , Disease Progression , Early Detection of Cancer , Esophageal Neoplasms , Humans , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Barrett Esophagus/genetics , Barrett Esophagus/pathology , Case-Control Studies , DNA/genetics , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Carcinogenesis/genetics , Whole Genome Sequencing , Cohort Studies , Biopsy , Oncogenes , Immunomodulation , DNA Copy Number Variations , Gene Amplification , Early Detection of Cancer/methods
5.
Gastroenterology ; 166(5): 872-885.e2, 2024 05.
Article in English | MEDLINE | ID: mdl-38320723

ABSTRACT

BACKGROUND & AIMS: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).


Subject(s)
Carcinoma, Pancreatic Ductal , Genetic Predisposition to Disease , Genetic Testing , Pancreatic Neoplasms , Patient Reported Outcome Measures , Telemedicine , Humans , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/psychology , Pancreatic Neoplasms/diagnosis , Male , Female , Middle Aged , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/psychology , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/therapy , Genetic Predisposition to Disease/psychology , Risk Assessment , Aged , Anxiety/psychology , Anxiety/diagnosis , Anxiety/etiology , Adult , Depression/diagnosis , Depression/genetics , Depression/psychology , Genetic Counseling/psychology , Germ-Line Mutation , Family/psychology
6.
Proc Natl Acad Sci U S A ; 119(47): e2213835119, 2022 11 22.
Article in English | MEDLINE | ID: mdl-36395141

ABSTRACT

Somatic copy number alterations (SCNAs), generally (1) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors (2); however, genomic regions mediating these effects are unclear and probably tissue specific. Previously, 9p21.3 loss was found to be an early genetic driver of human papillomavirus-negative (HPV-) head and neck squamous cancer (HNSC), associated with an immune-cold tumor microenvironment (TME) signal, and recent evidence suggested that this TME-cold phenotype was greatly enhanced with 9p21 deletion size, notably encompassing band 9p24.1 (3). Here, we report multi-omic, -threshold and continuous-variable dissection of 9p21 and 9p24 loci (including depth and degree of somatic alteration of each band at each locus, and each gene at each band) and TME of four HPV- HNSC cohorts. Preferential 9p24 deletion, CD8 T-cell immune-cold associations were observed, driven by 9p24.1 loss, and in turn by an essential telomeric regulatory gene element, JAK2-CD274. Surprisingly, same genetic region gains were immune hot. Related 9p21-TME analyses were less evident. Inherent 9p-band-level influences on anti-PD1 ICT survival rates, coincident with TME patterns, were also observed. At a 9p24.1 whole-transcriptome expression threshold of 60th percentile, ICT survival rate exceeded that of lower expression percentiles and of chemotherapy; below this transcript threshold, ICT survival was inferior to chemotherapy, the latter unaffected by 9p24.1 expression level (P-values < 0.01, including in a PD-L1 immunohistochemistry-positive patient subgroup). Whole-exome analyses of 10 solid-tumor types suggest that these 9p-related ICT findings could be relevant to squamous cancers, in which 9p24.1 gain/immune-hot associations exist.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Papillomavirus Infections , Humans , Tumor Microenvironment/genetics , Immune Checkpoint Inhibitors , Papillomavirus Infections/genetics , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/genetics , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics
7.
J Biol Chem ; 299(2): 102866, 2023 02.
Article in English | MEDLINE | ID: mdl-36596361

ABSTRACT

G proteins and G protein-coupled receptors activate a diverse array of signal transduction pathways that promote cell growth and survival. Indeed, hot spot-activating mutations in GNAQ/GNA11, encoding Gαq proteins, are known to be driver oncogenes in uveal melanoma (UM), for which there are limited effective therapies currently available. Focal adhesion kinase (FAK) has been recently shown to be a central mediator of Gαq-driven signaling in UM, and as a result, is being explored clinically as a therapeutic target for UM, both alone and in combination therapies. Despite this, the repertoire of Gαq/FAK-regulated signaling mechanisms have not been fully elucidated. Here, we used a whole-genome CRISPR screen in GNAQ-mutant UM cells to identify mechanisms that, when overactivated, lead to reduced sensitivity to FAK inhibition. In this way, we found that the PI3K/AKT signaling pathway represented a major resistance driver. Our dissection of the underlying mechanisms revealed that Gαq promotes PI3K/AKT activation via a conserved signaling circuitry mediated by FAK. Further analysis demonstrated that FAK activates PI3K through the association and tyrosine phosphorylation of the p85 regulatory subunit of PI3K and that UM cells require PI3K/AKT signaling for survival. These findings establish a novel link between Gαq-driven signaling and the stimulation of PI3K as well as demonstrate aberrant activation of signaling networks underlying the growth and survival of UM and other Gαq-driven malignancies.


Subject(s)
Carcinogenesis , Focal Adhesion Protein-Tyrosine Kinases , GTP-Binding Protein alpha Subunits, Gq-G11 , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Clustered Regularly Interspaced Short Palindromic Repeats , Focal Adhesion Protein-Tyrosine Kinases/genetics , Focal Adhesion Protein-Tyrosine Kinases/metabolism , GTP-Binding Protein alpha Subunits/metabolism , GTP-Binding Protein alpha Subunits, Gq-G11/genetics , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Humans , Carcinogenesis/genetics
8.
Proc Natl Acad Sci U S A ; 118(19)2021 05 11.
Article in English | MEDLINE | ID: mdl-33952700

ABSTRACT

An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV-) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3+ and CD8+ T cell microenvironments in precancer (mostly CD3+, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV- HNSC after anti-PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.


Subject(s)
Aneuploidy , Chromosome Deletion , Head and Neck Neoplasms/genetics , Immune Evasion , Papillomavirus Infections , Adult , Aged , Aged, 80 and over , B7-H1 Antigen , CD3 Complex , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Chromosomes , Cytokines , DNA Copy Number Variations , Gene Expression Regulation, Neoplastic , Genes, p53/genetics , Humans , Immune Evasion/genetics , Immunotherapy , Janus Kinase 2 , Middle Aged , Papillomavirus Infections/genetics , T-Lymphocytes, Cytotoxic , Tumor Microenvironment , Young Adult
9.
Cancer ; 129(5): 714-727, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36597662

ABSTRACT

BACKGROUND: Studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent/metastatic head and neck squamous cell carcinoma therapy. This study investigated the timing, influence of somatic copy-number alterations (SCNAs), and clinical implications of PD-L1 and immune-cell patterns in oral precancer (OPC). METHODS: The authors evaluated spatial CD3, CD3/8, and CD68 density (cells/mm2 ) and PD-L1 (membranous expression in cytokeratin-positive intraepithelial neoplastic cells and CD68) patterns by multiplex immunofluorescence in a 188-patient prospective OPC cohort, characterized by clinical, histologic, and SCNA risk factors and protocol-specified primary end point of invasive cancer. The authors used Wilcoxon rank-sum and Fisher exact tests, linear mixed effect models, mediation, and Cox regression and recursive-partitioning analyses. RESULTS: Epithelial, but not CD68 immune-cell, PD-L1 expression was detected in 28% of OPCs, correlated with immune-cell infiltration, 9p21.3 loss of heterozygosity (LOH), and inferior oral cancer-free survival (OCFS), notably in OPCs with low CD3/8 cell density, dysplasia, and/or 9p21.3 LOH. High CD3/8 cell density in dysplastic lesions predicted better OCFS and eliminated the excess risk associated with prior oral cancer and dysplasia. PD-L1 and CD3/8 patterns revealed inferior OCFS in PD-L1 high intrinsic induction and dysplastic immune-cold subgroups. CONCLUSION: This report provides spatial insight into the immune landscape and drivers of OPCs, and a publicly available immunogenomic data set for future precancer interrogation. The data suggest that 9p21.3 LOH triggers an immune-hot inflammatory phenotype; whereas increased 9p deletion size encompassing CD274 at 9p24.1 may contribute to CD3/8 and PD-L1 depletion during invasive transition. The inferior OCFS in PD-L1-high, immune-cold OPCs support the development of T-cell recruitment strategies.


Subject(s)
Head and Neck Neoplasms , Mouth Neoplasms , Humans , B7-H1 Antigen , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Genomics , Head and Neck Neoplasms/metabolism , Lymphocytes, Tumor-Infiltrating , Mouth Neoplasms/genetics , Mouth Neoplasms/metabolism , Neoplasm Recurrence, Local/metabolism , Prospective Studies , Squamous Cell Carcinoma of Head and Neck/metabolism , Tumor Microenvironment/genetics
10.
Nutr Cancer ; 74(1): 141-148, 2022.
Article in English | MEDLINE | ID: mdl-33511883

ABSTRACT

Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6-10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except ß-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), P-trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.


Subject(s)
Prostatic Neoplasms , Retinoids , Biopsy , Carotenoids , Humans , Inflammation , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/prevention & control , Vitamin A
11.
Lancet Oncol ; 22(6): 883-892, 2021 06.
Article in English | MEDLINE | ID: mdl-33989559

ABSTRACT

BACKGROUND: Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC. METHODS: This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants. FINDINGS: Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation. FUNDING: Merck Sharp & Dohme.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cetuximab/administration & dosage , Squamous Cell Carcinoma of Head and Neck/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen/genetics , Cetuximab/adverse effects , ErbB Receptors/genetics , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Programmed Cell Death 1 Receptor/genetics , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology
12.
Int J Cancer ; 146(12): 3450-3460, 2020 06 15.
Article in English | MEDLINE | ID: mdl-31782524

ABSTRACT

RAS alterations are often found in difficult-to-treat malignancies and are considered "undruggable." To better understand the clinical correlates and coaltered genes of RAS alterations, we used targeted next-generation sequencing (NGS) to analyze 1,937 patients with diverse cancers. Overall, 20.9% of cancers (405/1,937) harbored RAS alterations. Most RAS-altered cases had genomic coalterations (95.3%, median: 3, range: 0-51), often involving genes implicated in oncogenic signals: PI3K pathway (31.4% of 405 cases), cell cycle (31.1%), tyrosine kinase families (21.5%) and MAPK signaling (18.3%). Patients with RAS-altered versus wild-type RAS malignancies had significantly worse overall survival (OS; p = 0.02 [multivariate]), with KRAS alterations, in particular, showing shorter survival. Moreover, coalterations in both RAS and PI3K signaling or cell-cycle-associated genes correlated with worse OS (p = 0.004 and p < 0.0001, respectively [multivariate]). Among RAS-altered patients, MEK inhibitors alone did not impact progression-free survival (PFS), while matched targeted therapy against non-MAPK pathway coalterations alone showed a trend toward longer PFS (vs. patients who received unmatched therapy) (HR: 0.79, 95% CI: 0.61-1.03, p = 0.07). Three of nine patients (33%) given tailored combination therapies targeting both MAPK and non-MAPK pathways achieved objective responses. In conclusion, RAS alterations correlated with poor survival across cancers. The majority of RAS alterations were accompanied by coalterations impacting other oncogenic pathways. MEK inhibitors alone were ineffective against RAS-altered cancers while matched targeted therapy against coalterations alone correlated with a trend toward improved PFS. A subset of the small number of patients given MEK inhibitors plus tailored non-MAPK-targeting agents showed responses, suggesting that customized combinations warrant further investigation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Neoplasms/mortality , Protein Kinase Inhibitors/therapeutic use , ras Proteins/genetics , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacology , California/epidemiology , Female , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Male , Middle Aged , Molecular Targeted Therapy/methods , Mutation , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/pathology , Observational Studies as Topic , Precision Medicine , Prognosis , Progression-Free Survival , Protein Kinase Inhibitors/pharmacology , ras Proteins/metabolism
13.
Prostate ; 80(11): 895-905, 2020 08.
Article in English | MEDLINE | ID: mdl-32506665

ABSTRACT

BACKGROUND: Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer. METHODS: We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI). RESULTS: In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05). CONCLUSIONS: In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.


Subject(s)
Gonadal Steroid Hormones/blood , Prostatitis/blood , Aged , Biopsy , Body Weight , Cross-Sectional Studies , Humans , Male , Middle Aged , Placebos , Prostatic Neoplasms/prevention & control , Prostatitis/pathology , Randomized Controlled Trials as Topic
14.
Oncologist ; 25(11): e1803-e1806, 2020 11.
Article in English | MEDLINE | ID: mdl-32949172

ABSTRACT

BACKGROUND: Precision oncology uses molecular profiling of tumors to identify biomarker-tailored therapies for patients in the hope of improving outcomes. Typically, only a minority of patients receives evaluable matched treatment. This study explored the reasons for attrition on a precision medicine trial. MATERIALS AND METHODS: Study participants were 190 adult patients who consented to the I-PREDICT (Investigation of molecular Profile-Related Evidence Determining Individualized Cancer Therapy) trial. Patients had metastatic and/or unresectable incurable malignancies. Patients who were not evaluable were analyzed. RESULTS: Of consented patients, 44% were not evaluable. Men were twice as likely to be not evaluable as women. Prominently, 45% of patients who were not evaluable dropped off because of death, hospice referral, or decline in organ function. CONCLUSION: Health deterioration of consented patients is a significant barrier to being evaluable on the I-PREDICT trial. These data suggest that patients are enrolled on precision oncology trials too late in their disease course or with excessive disease burden.


Subject(s)
Neoplasms , Adult , Female , Humans , Male , Medical Oncology , Neoplasms/drug therapy , Precision Medicine
15.
Support Care Cancer ; 28(10): 4707-4720, 2020 Oct.
Article in English | MEDLINE | ID: mdl-31965306

ABSTRACT

PURPOSE: Lung cancer treatment can lead to negative health consequences. We analyzed the effects of curative-intent lung cancer treatment on functional exercise capacity (EC) and patient-reported outcomes (PROs). METHODS: We performed a prospective, observational cohort study of consecutive patients with stage I-IIIA lung cancer undergoing curative-intent therapy and assessed functional EC (primary outcome, six-minute walk distance (6MWD)), cancer-specific quality of life (QoL) (secondary outcome, European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC-QLQ-C30) summary score), and exploratory outcomes including dyspnea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)) and fatigue Brief Fatigue Inventory (BFI)) symptoms before and at 1 to 3 months post-treatment. We analyzed the time effect of treatment on outcomes using multivariable generalized estimating equations. RESULTS: In 35 enrolled participants, treatment was associated with a clinically meaningful and borderline-significant decline in functional EC ((mean change, 95% CI) 6MWD = - 25.4 m (- 55.3, + 4.47), p = 0.10), clinically meaningful and statistically significant higher dyspnea (UCSD SOBQ = + 13.1 (+ 5.7, + 20.6), p = 0.001) and fatigue (BFI = + 10.0 (+ 2.9, + 17.0), p = 0.006), but no clinically meaningful or statistically significant change in cancer-specific QoL (EORTC-QLQ-C30 summary score = - 3.4 (- 9.8, + 3.0), p = 0.30). CONCLUSIONS: Among the first prospective analysis of the effect of curative-intent lung cancer treatment on functional EC and PROs, we observed worsening dyspnea and fatigue, and possibly a decline in functional EC but not cancer-specific QoL at 1 to 3 months post-treatment. Interventions to reduce treatment-related morbidities and improve lung cancer survivorship may need to focus on reducing dyspnea, fatigue, and/or improving functional EC.


Subject(s)
Exercise Tolerance/physiology , Lung Neoplasms/physiopathology , Lung Neoplasms/therapy , Aged , Cohort Studies , Exercise/physiology , Fatigue/etiology , Fatigue/physiopathology , Female , Humans , Male , Middle Aged , Patient Reported Outcome Measures , Prospective Studies , Quality of Life , Surveys and Questionnaires
16.
Proc Natl Acad Sci U S A ; 113(39): 10750-8, 2016 09 27.
Article in English | MEDLINE | ID: mdl-27638202

ABSTRACT

Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system's ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative.


Subject(s)
Neoplasms/immunology , Neoplasms/prevention & control , Precancerous Conditions/pathology , Germ Cells/metabolism , Humans , Immune System/pathology , Models, Biological , Neoplasm Proteins/metabolism , Tumor Microenvironment
17.
Carcinogenesis ; 39(2): 125-133, 2018 02 09.
Article in English | MEDLINE | ID: mdl-29228205

ABSTRACT

Substantial preclinical data suggest estrogen's carcinogenic role in prostate cancer development; however, epidemiological evidence based on circulating estrogen levels is largely null. Compared with circulating estrogen, the intraprostatic estrogen milieu may play a more important role in prostate carcinogenesis. Using a nested case-control design in the Prostate Cancer Prevention Trial (PCPT), we examined associations of genetic variants of genes that are involved in estrogen synthesis, metabolism and function with prostate cancer risk. A total of 25 potentially functional single nucleotide polymorphisms (SNPs) in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined in whites only. Controls (n = 1380) were frequency matched to cases on age, PCPT treatment arm, and family history (n = 1506). Logistic regression models adjusted for age and family history were used to estimate odds ratios (OR) and 95% confidence intervals (CI) separately in the placebo and finasteride arms. SNPs associated with prostate cancer risk differed by treatment arm. The associations appeared to be modified by circulating estrogen and androgen levels. CYP19A1 was the only gene harboring SNPs that were significantly associated with risk in both the placebo and finasteride arms. Haplotype analysis with all three CYP19A1 SNPs genotyped (rs700518, rs2445765, rs700519) showed that risk-allele haplotypes are associated with the increased prostate cancer risk in both arms when comparing with the non-risk allele haplotype. In conclusion, associations between SNPs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment.


Subject(s)
Aromatase/genetics , Estrogens/metabolism , Genetic Predisposition to Disease/genetics , Prostatic Neoplasms/genetics , 5-alpha Reductase Inhibitors/therapeutic use , Aged , Case-Control Studies , Finasteride/therapeutic use , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Prostatic Neoplasms/prevention & control
18.
Support Care Cancer ; 26(7): 2459-2469, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29429006

ABSTRACT

PURPOSE: Lung cancer survivors are at risk for health impairments resulting from the effects and/or treatment of lung cancer and comorbidities. Practical exercise capacity (EC) assessments can help identify impairments that would otherwise remain undetected. In this study, we characterized and analyzed the association between functional EC and cancer-specific quality of life (QoL) in lung cancer survivors who previously completed curative intent treatment. METHODS: In a cross-sectional study of 62 lung cancer survivors who completed treatment ≥ 1 month previously, we assessed functional EC with the 6-min walk distance (6MWD) and cancer-specific QoL with the European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC-QLQ-C30). Cancer-specific QoL was defined using a validated composite EORTC-QLQ-C30 summary score. Univariable (UVA) and multivariable linear regression analyses (MVA) were performed to assess the relationship between functional EC and cancer-specific QoL. RESULTS: Lung cancer survivors had reduced functional EC (mean 6MWD = 335 m, 65% predicted) and QoL (mean EORTC-QLQ-C30 summary score = 77, scale range 0-100). In UVA, 6MWD was significantly associated with cancer-specific QoL (R2 = 0.16, p = 0.001). In MVA, in a final model that also included heart failure, obstructive sleep apnea, and psychiatric illness, 6MWD was independently associated with cancer-specific QoL (partial R2 = 0.20, p = 0.001). CONCLUSIONS: Functional EC was independently associated with cancer-specific QoL in lung cancer patients postcurative intent treatment. Exercise-based interventions aimed at improving EC may improve cancer-specific QoL in these patients.


Subject(s)
Exercise/physiology , Lung Neoplasms/psychology , Quality of Life/psychology , Aged , Cross-Sectional Studies , Female , Humans , Lung Neoplasms/pathology , Male , Neoplasm Staging , Patient Reported Outcome Measures , Surveys and Questionnaires , Survivorship
19.
J Oncol Pharm Pract ; 24(3): 229-231, 2018 04.
Article in English | MEDLINE | ID: mdl-28436313

ABSTRACT

While therapy with epidermal growth factor receptor inhibitors leads to meaningful clinical responses in several tumor types, it has also been linked with perplexing toxic effects. Skin effects of these agents such as generalized papulo-pustular rash, trichomegaly, fingertip fissures, xerosis, pruritus and paronichias are now well characterized. Though uncommon, nail atrophic changes have also been described in subjects treated with these classes of agents. We describe herein unusual longitudinal thumbnail fissures caused by erlotinib therapy for metastatic lung cancer. Unique features are bilateral thumbnail involvement and central location in the nail bed. This side effect of erlotinib has not been previously reported in the medical literature.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/adverse effects , Drug Eruptions , Erlotinib Hydrochloride/adverse effects , Lung Neoplasms/drug therapy , Nail Diseases/chemically induced , Protein Kinase Inhibitors/adverse effects , Adenocarcinoma/diagnosis , Adenocarcinoma of Lung , Antineoplastic Agents/therapeutic use , Drug Eruptions/diagnosis , Drug Eruptions/therapy , Erlotinib Hydrochloride/therapeutic use , Humans , Lung Neoplasms/diagnosis , Male , Middle Aged , Nail Diseases/diagnosis , Protein Kinase Inhibitors/therapeutic use , Thumb
20.
Lancet Oncol ; 18(8): e457-e471, 2017 08.
Article in English | MEDLINE | ID: mdl-28759385

ABSTRACT

The lifestyle factors of physical activity, sedentary behaviour, and diet are increasingly being studied for their associations with cancer. Physical activity is inversely associated with and sedentary behaviour is positively (and independently) associated with an increased risk of more than ten types of cancer, including colorectal cancer (and advanced adenomas), endometrial cancers, and breast cancer. The most consistent dietary risk factor for premalignant and invasive breast cancer is alcohol, whether consumed during early or late adult life, even at low levels. Epidemiological studies show that the inclusion of wholegrain, fibre, fruits, and vegetables within diets are associated with reduced cancer risk, with diet during early life (age <8 years) having the strongest apparent association with cancer incidence. However, randomised controlled trials of diet-related factors have not yet shown any conclusive associations between diet and cancer incidence. Obesity is a key contributory factor associated with cancer risk and mortality, including in dose-response associations in endometrial and post-menopausal breast cancer, and in degree and duration of fatty liver disease-related hepatocellular carcinoma. Obesity produces an inflammatory state, characterised by macrophages clustered around enlarged hypertrophied, dead, and dying adipocytes, forming crown-like structures. Increased concentrations of aromatase and interleukin 6 in inflamed breast tissue and an increased number of macrophages, compared with healthy tissue, are also observed in women with normal body mass index, suggesting a metabolic obesity state. Emerging randomised controlled trials of physical activity and dietary factors and mechanistic studies of immunity, inflammation, extracellular matrix mechanics, epigenetic or transcriptional regulation, protein translation, circadian disruption, and interactions of the multibiome with lifestyle factors will be crucial to advance this field.


Subject(s)
Diet , Exercise , Neoplasms/epidemiology , Obesity/epidemiology , Sedentary Behavior , Breast Neoplasms/epidemiology , Colorectal Neoplasms/epidemiology , Female , Health Behavior , Humans , Incidence , Liver Neoplasms/epidemiology , Male , Neoplasms/mortality , Pancreatic Neoplasms/epidemiology , Prostatic Neoplasms/epidemiology , Risk Factors
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