Somatic Genomics Research Articles

Here, There, and Everywhere: Somatic Genomics Uncovers DNA Variants to Inspire Drug Discovery

Here, There, and Everywhere: Somatic Genomics Uncovers DNA Variants to Inspire Drug Discovery

Utilizing Human Genetics to Develop Chemoprevention for Cancer-Too Good an Opportunity to be Missed.

Large-scale genetic studies are reliably identifying many risk factors for disease in the general population. Several of these genetic risk factors encode potential drug targets, and genetics has already helped to introduce targeted agents for some diseases, an example being lipid-lowering drugs to reduce the incidence of cardiovascular disease. Multiple drugs have been developed to treat cancers based on somatic mutations and genomics, but in stark contrast, there seems to be a reluctance to use germline genetic data to develop drugs to prevent malignancy, despite the large numbers of people who could benefit, the potential for lowering cancer rates, and the widespread current use of non-pharmaceutical measures to reduce cancer risk factors such as tobacco, alcohol, and infectious diseases. We argue that concerted efforts for cancer prevention based on genetics, including genes influenced by common polymorphisms that modulate cancer risk, are urgently needed. There are enormous, yet underutilized, opportunities to develop novel targeted agents for chemoprevention of cancer based on human germline genetics. Such efforts are likely to require the support of a dedicated funding program by national and international agencies. See related commentary by Winham and Sherman, p. 13.

Pharmacotypes across the Genomic Landscape of Pediatric Acute Lymphoblastic Leukemia and Impact on Treatment Response

INTRODUCTION The current paradigm of risk stratification in childhood acute lymphoblastic leukemia (ALL) utilizes a combination of clinical features, leukemia somatic genomics and early treatment response as measured by minimal residual disease (MRD). Although ALL subtypes and MRD are strongly related to treatment outcomes, the pharmacological basis of their prognostic impact remains incompletely understood. Therefore, we sought to characterize pharmacotypes (drug sensitivities) across the complete spectrum of ALL molecular subtypes and determine their association with in vivo treatment response and survival outcomes. METHODS This was a prospective study of 805 children with newly-diagnosed ALL from Total Therapy XV, XVI, and XVII trials at St Jude Children's Research Hospital. We performed ex vivo pharmacotyping of 18 drugs on primary ALL diagnostic blasts to determine drug sensitivities (LC50 - dose required to kill 50% of leukemia cells). RNA-sequencing was performed to derive molecular subtype. We then evaluated the associations of drug LC50 with clinical features, ALL subtype, MRD, and event-free survival (Figure 1). RESULTS We analyzed 5,447 drug measurements across 23 ALL subtypes. LC50s of prednisolone, asparaginase, and mercaptopurine were associated with age, and/or with leukocyte count at diagnosis. Sensitivities to 14 of 18 drugs varied across ALL molecular subtypes. For cytotoxic agents, B-ALL subtypes with favorable prognosis (ETV6-RUNX1 and hyperdiploidy) exhibited greatest sensitivity to asparaginase and glucocorticoids, whereas high-risk subtypes (KMT2A, BCR-ABL1, and BCR-ABL1-like) were resistant. Novel subtypes DUX4 and ETV6-RUNX1-like ALL showed significant resistance to cytotoxic drugs. For targeted agents, hyperdiploid ALL was most sensitive to venetoclax, whereas TCF3-PBX1, BCR-ABL1, and T-ALL were dasatinib-sensitive. The poor-prognosis ETP-ALL was resistant to most cytotoxic drugs compared to T-ALL. Although BCR-ABL1, BCR-ABL1-like, and CRLF2 are closely related transcriptionally, these three subtypes had distinctive drug sensitivity profiles. In B-ALL, sensitivities of prednisolone, asparaginase, dexamethasone, cytarabine and thiopurines were positively correlated with MRD. By contrast, these drugs were not correlated with MRD in T-ALL. Instead, sensitivities of dasatinib and nelarabine correlated positively, and venetoclax negatively, with MRD in T-ALL. Finally, we classified patients into six functional clusters based on ALL pharmacotypes, each with distinct patterns of somatic genomic aberrations and MRD response. Drug sensitivity cluster was significantly associated with event-free survival, even after adjusting for MRD. Importantly, pharmacotyping identified a T-ALL subset with poor prognosis under conventional chemotherapy but also with unique sensitivity to targeted agents, pointing to therapeutic intervention to improve survival in this group. CONCLUSIONEx vivo drug sensitivities vary widely across ALL subtypes and strongly influence in vivo MRD. Our study comprehensively described pharmacological heterogeneity of ALL and the association of drug sensitivities with survival outcomes, providing insight into the pharmacological basis of inter-patient variability in ALL treatment outcomes and highlighting opportunities for individualizing therapy for this blood cancer. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clonal Hematopoiesis Driven By MDM4 Amplification Defines a Canonical Route Towards Secondary MDS/AML in Fanconi Anemia Patients

IntroductionFanconi anemia (FA) is the most frequent inherited DNA-repair disease in human, driving hematopoietic stem cell (HSC) failure in children and a major predisposition to poor-prognosis myelodysplastic syndrome (MDS) and acute leukemia (AML) in children or young adults. MDS/AML secondary to FA have a dismal prognosis in this frail population with a high chemotherapy-related toxicity. How bone marrow (BM) cells progress to myeloid malignancies in a background of cell intrinsic genomic instability and stem cell exhaustion is still poorly understood. Here we aimed to identify the molecular and functional determinants of BM progression to MDS/AML in FA patients.MethodsWe studied a cohort of 335 FA patients, representing virtually all FA patients seen in France from 2002 to 2020. We performed longitudinal clinical studies (cytopenia, BM morphology and staging, HSCT, survival), somatic genomics (karyotype, myeloid cancer gene panel, aCGH, WES, WGS), expression analysis by RNAseq on clonal cells, and functional studies (gene modulation in HSPCs, transgenic MDM4 mice, CFU and competitive engraftment experiments). Paired clonal BM and skin fibroblasts samples were available for 62 MDS/AML FA patients; WES and WGS files from age-matched non FA MDS/AML were used as controls.Results98 out of 335 patients (29%) experienced clonal evolution, first seen at a median age of 13y, including 51 (15%) with blastic evolution (>5% BM blasts, median age 16y). Unbalanced chromosomal translocations rather than point mutations underlaid clonal evolution in comparison to age-matched, sporadic (non-FA) AML cases. The most prominent driver lesion was chromosome 1q duplication (1q+), found in 52% of the clonal FA patients, while other recurrent lesions were gain of 3q (3q+/EVI1; 40%), translocations/del/mut involving the RUNX1 gene (35%), monosomy 7/7q- (31%), and signaling gene mutations (18%). Based on longitudinal studies and ranking models, we evidenced that 1q+ occurred early, yielding preleukemic clonal hematopoiesis, whereas 3q+, -7/del7q, RUNX1 and signaling mutations occurred later along with BM transformation.Regarding genomic instability, WGS analysis of FA AML cells revealed a unique mutational signature that shares features with BRCA-related solid cancers [homologous recombination deficient (HRD)-type substitution signature, accumulation of small/intermediate-size deletions and large structural variants (SV)]. SV breakpoint analysis identified microhomology-mediated end joining (MM-EJ, also known as Alt-EJ) as the preferential DNA repair mechanism in the FA context. Specifically, a fragile site in the 1q pericentromeric repeated region underlaid 1q+ translocations.Next, we found that the MDM4 oncogene, a negative modulator of p53 response located in the minimal 1q duplicated region, was overexpressed in 1q+ but not in clonal non-1q FA cells. We hypothesized that 1q+ may attenuate the FA-associated p53 pathway hyperactivation through increased gene dosage of MDM4. Consistently, RNA-seq of patient cells before and after clonal progression showed p53 pathway activation before clonal evolution and subsequent p53 downregulation along with 1q+. When evaluated in vitro by CFU assay, lentiviral overexpression of MDM4 rescued clonogenicity defect of HSCPs from both FA patients and Fanc-/- mice, at the same level as TP53 knockdown. We produced a transgenic mouse bearing a duplicated Mdm4 locus and showed that MdM4 overexpression conferred an advantage to FA-like HSPCs in competitive transplant experiments, modeling clonal hematopoiesis. Exposure of 1q+ FA cells to Mdm4 inhibitors raised therapeutic potential.ConclusionsThe somatic genomic landscape of FA MDS/AML reveals a unique FA mutational signature, characterized by structural rearrangements and copy number abnormalities rather than point mutations. Our results define a canonical oncogenic route towards secondary MDS/AML in FA patients, in which the early modulation of the p53 pathway through 1q+/MDM4 oncogene overexpression plays a pivotal role, raising novel monitoring and therapeutic prospects for the FA patients. DisclosuresSebert: BMS: Consultancy; Abbvie: Consultancy. Dalle: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding.

368P Characteristics of deleterious germline mutations in glioma patients

Glioma is the most common primary central nervous system (CNS) tumor with the highest incidence rate and mortality. The genetic basis of glioma has been found in somatic genomics research, but the characteristics of germline mutations have not been fully elucidated. Here, we reported an analysis of genomic features in 35 glioma patients (pts) with autosomal-dominant inheritance of germline mutations.

DriveR: a novel method for prioritizing cancer driver genes using somatic genomics data

BackgroundCancer develops due to “driver” alterations. Numerous approaches exist for predicting cancer drivers from cohort-scale genomics data. However, methods for personalized analysis of driver genes are underdeveloped. In this study, we developed a novel personalized/batch analysis approach for driver gene prioritization utilizing somatic genomics data, called driveR.ResultsCombining genomics information and prior biological knowledge, driveR accurately prioritizes cancer driver genes via a multi-task learning model. Testing on 28 different datasets, this study demonstrates that driveR performs adequately, achieving a median AUC of 0.684 (range 0.651–0.861) on the 28 batch analysis test datasets, and a median AUC of 0.773 (range 0–1) on the 5157 personalized analysis test samples. Moreover, it outperforms existing approaches, achieving a significantly higher median AUC than all of MutSigCV (Wilcoxon rank-sum test p < 0.001), DriverNet (p < 0.001), OncodriveFML (p < 0.001) and MutPanning (p < 0.001) on batch analysis test datasets, and a significantly higher median AUC than DawnRank (p < 0.001) and PRODIGY (p < 0.001) on personalized analysis datasets.ConclusionsThis study demonstrates that the proposed method is an accurate and easy-to-utilize approach for prioritizing driver genes in cancer genomes in personalized or batch analyses. driveR is available on CRAN: https://cran.r-project.org/package=driveR.

The somatic mutation landscape of germline CHEK2-altered prostate cancer.

5084 Background: The intersection between germline and somatic genomics is an evolving field in which germline mutations may predispose to unique patterns of subsequent somatic mutations in cancer. Germline mutations in CHEK2, involved in cell cycle regulation and DNA damage response, are associated with an increased risk of prostate cancer (PCa), while somatic-only CHEK2 alterations in PCa are rare. The association of germline CHEK2 (g CHEK2)-altered PCa with somatic mutations is unknown, and may inform hypotheses about the etiology of these cancers. Methods: Germline DNA sequencing of 1,042 consecutive PCa patients (pts) from the public SignalDB database (www.signaldb.org) was analyzed for prevalence of pathogenic g CHEK2 mutations and was compared to individuals from the general population estimated by the ExAC database (containing 53,105 germline exomes). A separate cohort of 33 PCa pts from Johns Hopkins (JH) with known g CHEK2 mutations and available somatic tumor DNA sequencing (from primary prostatic tissue) was used to assess the association of g CHEK2 mutations with somatic mutations in genes that are recurrently altered in PCa ( TP53, RB1, PTEN, ATM, BRCA1/2, and CDK12); the prevalence of these somatic alterations was compared to those in 333 unselected PCa pts from the TCGA cohort. Somatic biallelic inactivation of CHEK2 was analyzed in a subset of pts. After uncovering a potential link between g CHEK2 and somatic CDK12 mutations, we studied a cohort of 69 pts with somatic CDK12 mutations where germline data were also available. Results: 28 of 1,042 (2.7%) PCa pts from SignalDB had a pathogenic g CHEK2 mutation, compared to a population prevalence (in ExAC) of 1.4% (750 of 53,105) (RR 1.9, 95%CI 1.3–2.8, P&lt; 0.001). Strikingly, only 23.8% of pts from SignalDB with g CHEK2 mutations had biallelic inactivation in the tumor . Furthermore, none of the 33 g CHEK2 pts from the JH cohort had evidence of somatic LOH. There were no differences in mutation prevalences involving TP53, RB1, PTEN, ATM, and BRCA1/2 between g CHEK2-altered and non-altered PCa pts. Unexpectedly, 5 of 33 (15%) g CHEK2-altered pts from the JH cohort had a somatic CDK12 mutation, compared to only 3 of 333 CDK12 mutations (1%) in unselected PCa pts from the TCGA cohort (RR 16.8, 95%CI 4.2–67, P&lt; 0.001). Conversely, 11 of 69 (16%) pts with a somatic CDK12 mutation harbored a pathogenic g CHEK2 mutation, compared to 28 of 1,042 (2.7%) unselected PCa pts from SignalDB (RR 5.9, 95%CI 3.1–11.4, P&lt; 0.001). Conclusions: Prostate cancers from g CHEK2-altered pts are infrequently characterized by biallelic CHEK2 inactivation and may be enriched for somatic CDK12 mutations, suggesting a unique mechanism of carcinogenesis that is different from g BRCA2-altered pts. Conversely, somatic CDK12-mutated cancers may be enriched for g CHEK2 mutations. The co-occurrence of CHEK2 and CDK12 mutations suggests a synergistic role in promoting cancer growth.

Genetics of pheochromocytoma and paraganglioma.

This review summarizes our current understanding of germline and somatic genetics and genomics of pheochromocytomas and paragangliomas (PCC/PGL), describes existing knowledge gaps, and discusses future research directions. Germline pathogenic variants (PVs) are found in up to 40% of those with PCC/PGL. Tumors with germline PVs are broadly categorized as Cluster 1 (pseudohypoxia), including those with SDH, VHL, FH, and EPAS1 PVs, or Cluster 2 (kinase signaling) including those with NF1, RET, TMEM127, and MAX PVs. Somatic driver mutations exist in some of the same genes (RET, VHL, NF1, EPAS1) as well as in additional genes including HRAS, CSDE1 and genes involved in cell immortalization (ATRX and TERT). Other somatic driver events include recurrent fusion genes involving MAML3. PCC/PGL have the highest association with germline PVs of all human solid tumors. Expanding our understanding of the molecular pathogenesis of PCC/PGL is essential to advancements in diagnosis and surveillance and the development of novel therapies for these unique tumors.

Germline and Somatic Genomics in Ribosomopathies

Germline and Somatic Genomics in Ribosomopathies

Next-Generation Sequencing and the Clinical Oncology Workflow: Data Challenges, Proposed Solutions, and a Call to Action.

Next-generation sequencing (NGS) of tumor and germline DNA is foundational for precision oncology, with rapidly expanding diagnostic, prognostic, and therapeutic implications. Although few question the importance of NGS in modern oncology care, the process of gathering primary molecular data, integrating it into electronic health records, and optimally using it as part of a clinical workflow remains far from seamless. Numerous challenges persist around data standards and interoperability, and clinicians frequently face difficulties in managing the growing amount of genomic knowledge required to care for patients and keep up to date. This review provides a descriptive analysis of genomic data workflows for NGS data in clinical oncology and issues that arise from the inconsistent use of standards for sharing data across systems. Potential solutions are described. NGS technology, especially for somatic genomics, is well established and widely used in routine patient care, quality measurement, and research. Available genomic knowledge bases play an evolving role in patient management but lack harmonization with one another. Questions about their provenance and timeliness of updating remain. Potentially useful standards for sharing genomic data, such as HL7 FHIR and mCODE, remain primarily in the research and/or development stage. Nonetheless, their impact will likely be seen as uptake increases across care settings and laboratories. The specific use case of ASCO CancerLinQ, as a clinicogenomic database, is discussed. Because the electronic health records of today seem ill suited for managing genomic data, other solutions are required, including universal data standards and applications that use application programming interfaces, along with a commitment on the part of sequencing laboratories to consistently provide structured genomic data for clinical use.

Somatic and germline genomics in paediatric acute lymphoblastic leukaemia.

Advances in genomic research and risk-directed therapy have led to improvements in the long-term survival and quality of life outcomes of patients with childhood acute lymphoblastic leukaemia (ALL). The application of next-generation sequencing technologies, especially transcriptome sequencing, has resulted in the identification of novel molecular subtypes of ALL with prognostic and therapeutic implications, as well as cooperative mutations that account for much of the heterogeneity in clinical responses observed among patients with specific ALL subtypes. In addition, germline genetic variants have been shown to influence the risk of developing ALL and/or the responses of non-malignant and leukaemia cells to therapy; shared pathways for drug activation and metabolism are implicated in treatment-related toxicity and drug sensitivity or resistance, depending on whether the genetic changes are germline, somatic or both. Indeed, although once considered a non-hereditary disease, genomic investigations of familial and sporadic ALL have revealed a growing number of genetic alterations or conditions that predispose individuals to the development of ALL and treatment-related second cancers. The identification of these genetic alterations holds the potential to direct genetic counselling, testing and possibly monitoring for the early detection of ALL and other cancers. Herein, we review these advances in our understanding of the genomic landscape of childhood ALL and their clinical implications.

Abstract IA20: Immunotherapy: Biomarkers and checkpoint blockade in NSCLC

Abstract Immunotherapy approaches targeting the PD-1 pathway have shown some clinical benefits in a fraction of patients with lung cancer, but expression of PD-L1 has proved to be an imperfect biomarker of efficacy. Recent studies have shown that tumor mutation burden (TMB) is also correlated with outcome and that it appears to be independent of PD-L1. TMB, however, only indirectly measures the number of neoantigenic peptides presented on tumor cell surface class I MHC, and predicted MHC matches may be an even better predictor of benefit. In addition, mutations in genes such as LKB1 may modulate the immune response, and mutations in the antigen presentation pathway may block it altogether. Mutations in DNA repair pathway genes may increase the number of potential neoantigens. Analysis of non-PD-1 pathway immunomodulators, immune cell infiltration, microenvironmental and microbiomic context, together with in-depth analysis of tumor somatic genomics, could lead to better patient selection for immunotherapy. Citation Format: David P. Carbone, Michael Sharpnack, Kai He. Immunotherapy: Biomarkers and checkpoint blockade in NSCLC [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA20.

Bael tree (Aegle marmelos (L.) Corrêa): importance, biology, propagation, and future perspectives

Major advances have been made in our understanding of the biology and biotechnology of the bael tree (Aegle marmelos), which is used for marmalade and has other applications. Aegle marmelos (L.) Correa (Rutaceae), popularly known as bael fruit or stone apple tree, and the basis of marmalade, is a deciduous tree with extensive medicinal, pharmacological, ethnomedicinal and conventional properties and uses. Aegle marmelos shows wide ecophysiological plasticity, including resistance to high temperature stress, while salt-resistant cultivars also exist. Its ability to grow in a wide range of soil pH makes A. marmelos an economically viable fruit tree for otherwise difficult-to-culture environments, and its adaptability to various ecological niche makes it an excellent candidate for agro-forestry and the reclamation of waste lands, but the choice of breeding parents for cross-pollinated experiments can affect fruit set. The micropropagation of A. marmelos offers an opportunity to conserve, through large-scale propagation, elite genotypes, although greater exploration of genotype collections is required to identify superior germplasm. This review explores the importance, adaptive physiology, disease and pest management, genetic diversity, conventional propagation and the use of tissue culture to propagate A. marmelos, either through direct or indirect organogenesis, or through somatic embryogenesis, genomics and future perspectives.

Somatic embryogenesis-related gene expression and functional genomics in mangosteen

The atypical somatic embryogenesis of mangosteen leads us to enquire what is happening at each stage of somatic embryogenesis (SE) at the level of the molecular regulation controlling transition between embryogenic stages. The expression of selected genes somatic embryogenesis receptor-like kinase 1 (SERK1), brassinosteroid insensitive 1-associated kinase 1 (BAK1)/SERK3, brassinosteroid insensitive 1 (BRI1), Leafy cotyledon 1 (LEC1) and Wuschel (WUS) were examined during the stages of SE in mangosteen. Somatic embryos of mangosteen were induced on Murashige and Skoog medium with 3.08 μM 6-benzylaminopurine, 3.18 μM thidiazurone and 60 mg/L glucose. Selected genes were isolated from early, mid and late globular stages of somatic embryo development. Quantitative PCR analyses showed that the early globular stage is characterised by low level of expression of SERK1, BRI1 and WUS and no expression of LEC1. The mid globular stage is characterised by a higher level of expression of the SERK1 and BRI1 genes, while the late globular stage is characterised by a high level of expression of LEC1 and WUS genes with low expression of the BRI1 gene. This demonstrates a clear match between globular stages and the expression of key genes at each stage. Transcriptome data from embryogenic structures showed differentially expressed genes involved in hypothetical signal transduction (brassinosteroid, auxin, cytokinin, jasmonic acid, abscisic acid and glucose) and biosynthetic (glucose and polyamine) pathways. The five selected genes showed interconnection with differentially expressed unigenes (up-regulated) indicating molecular interaction involved in somatic embryogenesis of mangosteen.

Mutational Signatures in Cancer (MuSiCa): a web application to implement mutational signatures analysis in cancer samples

BackgroundMutational signatures have been proved as a valuable pattern in somatic genomics, mainly regarding cancer, with a potential application as a biomarker in clinical practice. Up to now, several bioinformatic packages to address this topic have been developed in different languages/platforms. MutationalPatterns has arisen as the most efficient tool for the comparison with the signatures currently reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. However, the analysis of mutational signatures is nowadays restricted to a small community of bioinformatic experts.ResultsIn this work we present Mutational Signatures in Cancer (MuSiCa), a new web tool based on MutationalPatterns and built using the Shiny framework in R language. By means of a simple interface suited to non-specialized researchers, it provides a comprehensive analysis of the somatic mutational status of the supplied cancer samples. It permits characterizing the profile and burden of mutations, as well as quantifying COSMIC-reported mutational signatures. It also allows classifying samples according to the above signature contributions.ConclusionsMuSiCa is a helpful web application to characterize mutational signatures in cancer samples. It is accessible online at http://bioinfo.ciberehd.org/GPtoCRC/en/tools.html and source code is freely available at https://github.com/marcos-diazg/musica.

Incidence, persistence and determinants of human papillomavirus: A prospective cohort study of 10,000 HIV-negative Nigerian women.

1510 Background: Cervical cancer is the second commonest cancer in Africa. Persistent High-risk HPV (HRHPV) infection is a necessary cause but little is known about the persistence and associated risk factors of HRHPV infection in African women. The aim of this study was to determine risk factors and incidence of HPV infection in Nigerian women. Methods: ACCME is a multicenter prospective cohort study of host germline, cervical somatic and HRHPV genomics, epigenomics, and vaginal microenvironment; and their association with HPV. From February/2014 to January/2016, 10,000 HIV-negative women were enrolled into the cohort and are being followed up every 6 months. We used SPF25/LiPA10to characterize HPV infection and defined persistent infection as 2 consecutive positive tests done at least 12 months apart. Logistic regression models were used to estimate the associations between risk factors and persistent HPV. Results: The mean (SD) age of the study participants at baseline was 40 (10) years and the mean (SD) vaginal pH was 5.2 (0.6). About 42% of the participants were positive for any HPV positive and 21% had persistence of any HPV infections. Some, 35% of the participants had multiple infections with any HPV. About 54% of those with persistent any HPV infections had HRHPV; HPV types 52 (25%) and 18 (15%) were the most prevalent and persistent HRHPV types. The incidence of any HPV infection was 6.6/1,000 person-months while that of HRHPV was 2.6/1,000 person-months. Age, body mass index, level of education, marital and socio-economic status and total number of lifetime sexual partners were associated with HPV infection in these women. Conclusions: We defined the incidence, risk factors and commonest types of HRHPV in a large cohort of women in West Africa.

Incidence, Persistence, and Determinants of Human Papillomavirus: A Prospective Cohort Study of HIV-Negative Nigerian Women

Abstract 63 Background: Cervical cancer is the second most common cancer in Africa. Persistent high-risk human papillomavirus (HRHPV) infection is a necessary cause but little is known about the persistence and associated risk factors of HRHPV infection in African women. We undertook this work to determine risk factors and the incidence of HPV infection in Nigerian women. Methods: ACCME is a multicenter, prospective cohort study of host germline, cervical somatic and HRHPV genomics, epigenomics, and vaginal microenvironment and their association with HPV. From February 2014 to January 2016, 10,000 HIV-negative women were enrolled in the cohort and are being observed every 6 months. We used SPF25/LiPA10 to characterize HPV infection and defined persistent infection as two consecutive positive tests performed at least 12 months apart. Logistic regression models were used to estimate associations between risk factors and persistent HPV. Results: The mean (± standard deviation) age of study participants at baseline was 40 (± 10) years, and mean (± standard deviation) vaginal pH was 5.2 (± 0.6). Approximately 42% of participants were positive for any HPV and 21% had persistence of any HPV infection. Some (35%) participants had multiple infections with any HPV. Approximately 54% of those with persistent any HPV infection had HRHPV—HPV type 52 (25%) and type 18 (15%) were the most prevalent and persistent HRHPV types. Incidence of any HPV infection was 6.6 per 1,000 person-months, whereas that of HRHPV was 2.6 per 1,000 person-months. Age, body mass index, education level, marital and socioeconomic status, and total number of lifetime sexual partners were associated with HPV infection in these women. Conclusion: We defined the incidence, risk factors, and most common types of HRHPV in a large cohort of women in West Africa. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Sally N. Adebamowo No relationship to disclose Michael Odutola No relationship to disclose Ayotunde Famooto No relationship to disclose Eileen Dareng No relationship to disclose Amos Adebayo No relationship to disclose Peter Achara No relationship to disclose Bunmi Alabi No relationship to disclose Kayode Obende No relationship to disclose Richard Offiong No relationship to disclose Sanni Ologun No relationship to disclose Clement A. Adebamowo Speakers' Bureau: Merck

SC31.02 The Role of Patient Advocacy Groups

The role of Patient Advocacy organizations in the oncology health care delivery ecosystem is ever evolving and has moved well beyond its original role of solely advocating for services, research, care and understanding. The current field of patient advocacy has its roots in the patient rights movement of the 1970’s with groups like The National Welfare Rights Organization being instrumental in getting a patient bill of rights accepted by the Joint Commission on Accreditation of Healthcare Organizations in 1972.1 The transformation was further accelerated in 1991 with the formation of the FDA Patient Representative Program and has continued to expand over time with patient advocates now being involved in the entire care continuum. In this presentation I will focus my attention on examples of the ever evolving and expanding role of patient advocacy highlighted by projects developed and led by “partner” foundations the Bonnie J. Addario Lung Cancer Foundation (ALCF) and the Addario Lung Cancer Medical Institute (ALCMI). The disparities in lung cancer treatment and outcomes among underserved populations are well documented.2 Further, 80% of cancer patients are treated in the community hospital setting yet may not receive the same level of care as those treated at leading academic centers. The ALCF Community Hospital Centers of Excellence (COE) program addresses this unmet need. The COE program is a patient-centric model for lung cancer that establishes a standard of care for community hospitals which often treat underserved patient populations. The COE program, which currently includes 13 hospitals in regions of high unmet need, aims to improve the standard of care, patient experience and patient outcome by offering patients and caregivers the same type of multi-disciplinary and comprehensive care provided at leading academic centers. ALCF also provides lung cancer education and services to patients, caregivers and the community. The COE program tracks patient process data longitudinally for multiple quality-of-care metrics, including disease stage at diagnosis; molecular testing; tumor board review; time from diagnosis to treatment; treatment type; and clinical trial participation. Site data will also be monitored to provide a contextual picture of the program including total patients seen, demographics, insurance mix, rates and outcomes of molecular testing among other metrics. Data is analyzed across the COE community and against comparator groups to demonstrate impact of the COE program.3 The U.S. National Institutes of Health database currently lists over 45,000 cancer-related clinical trials worldwide.4 Unfortunately, more than 20% of these trials will never complete, for reasons unrelated to the effectiveness of the intervention that’s being tested. The most common reason for 20% of all clinical trials never finishing is poor patient accrual. One of the most common reasons for low accrual is procedural inefficiencies such as complexities in enrolling in the trial itself and the informed consent process. In 2014, ALCMI launched a prospective study to characterize somatic and germline genomics of adolescents and young adult (AYA) patients.5 It is estimated that less than 2% of those newly diagnosed with lung cancer globally are AYA, thus presenting a striking recruitment challenge. To address this challenge, ALCMI's study workflow included building a dedicated website3 enabling remote screening and e-consenting so patients could participate from their homes anywhere in the world while, in parallel, ALCF employed social media to educate patients on the importance of comprehensive genomic profiling and increasing awareness of the study via grass-roots patient blogging. Together, ALCMI and ALCF bring “research to the patient.” Accrual opened July 23, 2014 and in the first 5 weeks of the study, 37 subjects consented. Of the 37 initially consented, 35 enrolled via the remote web-portal. As of June 15 2016, 104 subjects are enrolled (128 consented) in the study from 10 countries following a social media campaign. Of the 104 subjects enrolled to date, 49% entered the study via the remote study portal with the balance recruited locally by participating ALCMI study sites. As briefly outlined above, patient advocacy organizations have moved well beyond their original patient supportive role and have become key players in the oncology healthcare delivery and clinical research ecosystems. As the healthcare system continues to evolve and become more complex so will the role of patient advocacy organizations. To address these challenges, there will be even greater need for innovation, sharing of data and resources, increased infrastructure and mission sophistication, the need to avoid overlap and duplication, and a laser focus on providing meaningful improvement in the availability, transparency and affordability of healthcare.

P3.06-008 Employing Remote Web Consenting and Social Media to Facilitate Enrollment to an International Trial on Young Lung Cancer: Topic: Others

In 2014, the Addario Lung Cancer Medical Institute (ALCMI) launched a prospective study to characterize somatic and germline genomics of adolescents and young adult (AYA) patients under the hypothesis that lung cancer diagnosis at younger ages (<40) are more likely to have targetable genomic alterations. It is estimated that less than 2% of those newly diagnosed with lung cancer globally are AYA, thus presenting a striking recruitment challenge. The study workflow includes a dedicated website enabling e-consenting so patients can participate remotely from anywhere in the world, including the underserved, and employs social media to share our trial. We have an integrated data and bio repository that allows for seamless communication and completion of study activities including routing of blood and tumor specimens. ALCMI's “sister” foundation, the Bonnie J. Addario Lung Cancer Foundation, played a key role in educating patient and caregiver communities, including a social media campaign. Accrual opened July 23, 2014. In the first 5 weeks of the study, 37 subjects consented versus the 5 projected. Of the 37 initially consented, 35 enrolled via the remote web-portal. As of June 15 2016, 104 subjects are enrolled (128 consented) in the study from 10 countries following a social media campaign of 89 discrete postings resulting in 21,062 active users out of 391,222 individual viewers and 675,680 impressions. Of the 104 subjects enrolled to date, 49% entered the study via the remote study portal with the balance recruited locally by participating ALCMI study sites. 45% of total accruals to date resulted from the education outreach by patient advocacy and patient to patient social networking. This study clearly demonstrates the utility, speed and feasibility of remote, web-based screening and consenting platforms supported by patient-centric, advocate-driven social media efforts as novel approaches to “bringing research to the patient” for global clinical trials.

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study.

BackgroundLung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression.Methods and FindingsWe performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10−50). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10−4) were associated with increased risk of distant metastasis. Our study’s limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality.ConclusionsThese data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD’s high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes.