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Papers by Elaine Mardis

Nature reviews. Clinical oncology, 2018

The combination of next-generation sequencing and advanced computational data analysis approaches... more The combination of next-generation sequencing and advanced computational data analysis approaches has revolutionized our understanding of the genomic underpinnings of cancer development and progression. The coincident development of targeted small molecule and antibody-based therapies that target a cancer's genomic dependencies has fuelled the transition of genomic assays into clinical use in patients with cancer. Beyond the identification of individual targetable alterations, genomic methods can gauge mutational load, which might predict a therapeutic response to immune-checkpoint inhibitors or identify cancer-specific proteins that inform the design of personalized anticancer vaccines. Emerging clinical applications of cancer genomics include monitoring treatment responses and characterizing mechanisms of resistance. The increasing relevance of genomics to clinical cancer care also highlights several considerable challenges, including the need to promote equal access to genomi...

British journal of cancer, Jan 6, 2018

Insights into the molecular pathogenesis of breast cancer might come from molecular analysis of t... more Insights into the molecular pathogenesis of breast cancer might come from molecular analysis of tissue from early stages of the disease. We conducted a case-control study nested in a cohort of women who had biopsy-confirmed benign breast disease (BBD) diagnosed between 1971 and 2006 at Kaiser Permanente Northwest and who were followed to mid-2015 to ascertain subsequent invasive breast cancer (IBC); cases (n = 218) were women with BBD who developed subsequent IBC and controls, individually matched (1:1) to cases, were women with BBD who did not develop IBC in the same follow-up interval as that for the corresponding case. Targeted sequence capture and sequencing were performed for 83 genes of importance in breast cancer. There were no significant case-control differences in mutation burden overall, for non-silent mutations, for individual genes, or with respect either to the nature of the gene mutations or to mutational enrichment at the pathway level. For seven subjects with DNA fr...

Blood cancer journal, Jan 21, 2018

Multiple myeloma (MM) is a disease of copy number variants (CNVs), chromosomal translocations, an... more Multiple myeloma (MM) is a disease of copy number variants (CNVs), chromosomal translocations, and single-nucleotide variants (SNVs). To enable integrative studies across these diverse mutation types, we developed a capture-based sequencing platform to detect their occurrence in 465 genes altered in MM and used it to sequence 95 primary tumor-normal pairs to a mean depth of 104×. We detected cases of hyperdiploidy (23%), deletions of 1p (8%), 6q (21%), 8p (17%), 14q (16%), 16q (22%), and 17p (4%), and amplification of 1q (19%). We also detected IGH and MYC translocations near expected frequencies and non-silent SNVs in NRAS (24%), KRAS (21%), FAM46C (17%), TP53 (9%), DIS3 (9%), and BRAF (3%). We discovered frequent mutations in IGLL5 (18%) that were mutually exclusive of RAS mutations and associated with increased risk of disease progression (p = 0.03), suggesting that IGLL5 may be a stratifying biomarker. We identified novel IGLL5/IGH translocations in two samples. We subjected 15 ...

Cold Spring Harbor molecular case studies, Jan 13, 2018

As in other brain tumors, multiple recurrences after complete resection and irradiation of suprat... more As in other brain tumors, multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. This standard-of-care treatment was established in the pre-genomic era without the ability to evaluate the effect that mutagenic therapies may exert on tumor evolution and in promoting resistance, recurrence, and death. We seized a rare opportunity to characterize treatment effects and the evolution of a single patient's ependymoma across four recurrences after different therapies. A combination of high depth whole genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were employed. Treatment with radiation and chemotherapies resulted in a substantial increase in mutational burden and diversification of the tumor subclonal architecture without eradication of the founding clone. Notable somatic alterations included a MEN1 driver...

Cold Spring Harbor molecular case studies, Jan 6, 2018

Gangliogliomas [WHO grade I] are rare tumors affecting the central nervous system and are most fr... more Gangliogliomas [WHO grade I] are rare tumors affecting the central nervous system and are most frequently observed in children. Genome sequencing of tumors is being utilized at an increasing rate in both research and clinical settings to characterize the genetic factors that drive tumorigenesis. Here, we report a rare BRAF somatic mutation (NM_004333.4:c.1794_1796dupTAC; p.Thr599dup) in the tumor genome from a pediatric patient in her late teens, who was initially diagnosed with low-grade ganglioglioma at age 13. This duplication of three nucleotides duplicates the threonine residue at amino acid 599 of the BRAF protein. Based on previous studies, this variant is likely to increase kinase activity, similar to the well-characterized BRAF p.Val600Glu (V600E) pathogenic variant. In addition, while the p.T599dup somatic mutation has been documented rarely in human cancers, the variant has not been previously reported in ganglioglioma. The identification of this variant presents an oppor...

Clinical Cancer Research, 2017

Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen re... more Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistr...

Cold Spring Harbor Symposia on Quantitative Biology, 2016

Nature genetics, Jan 31, 2017

CIViC is an expert-crowdsourced knowledgebase for Clinical Interpretation of Variants in Cancer d... more CIViC is an expert-crowdsourced knowledgebase for Clinical Interpretation of Variants in Cancer describing the therapeutic, prognostic, diagnostic and predisposing relevance of inherited and somatic variants of all types. CIViC is committed to opensource code, open-access content, public application programming interfaces (APIs) and provenance of supporting evidence to allow for the transparent creation of current and accurate variant interpretations for use in cancer precision medicine.

Cancer discovery, Nov 28, 2016

We present the case of a patient with a left frontal glioblastoma with PNET features and hypermut... more We present the case of a patient with a left frontal glioblastoma with PNET features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with Pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of Pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion suggestive of active CNS immunosurveillance following checkpoint blockade therapy.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Nov 2, 2016

Common variants have been associated with prostate cancer risk. Unfortunately, few are reproducib... more Common variants have been associated with prostate cancer risk. Unfortunately, few are reproducibly linked to aggressive disease, the phenotype of greatest clinical relevance. One possible explanation is that rare genetic variants underlie a significant proportion of the risk for aggressive disease. To identify such variants, we performed a two staged approach using whole exome sequencing followed by targeted sequencing of 800 genes in 652 aggressive prostate cancer patients and 752 disease-free controls in both African and European Americans. In each population, we tested rare variants for association using two gene-based aggregation tests. We established a study-wide significance threshold of 3.125 x 10-5 to correct for multiple testing. TET2 in African-Americans was associated with aggressive disease with 24.4% of cases harboring a rare deleterious variant compared to 9.6% of controls (FET p = 1.84x10-5, OR=3.0; SKAT-O p= 2.74x10-5). We report 8 additional genes with suggestive e...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 12, 2015

This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy o... more This trial was conducted to determine the maximum tolerated dose (MTD) and preliminary efficacy of buparlisib, an oral pan-class I PI3K inhibitor, plus fulvestrant in postmenopausal women with metastatic estrogen receptor positive breast cancer (ER+BC). Phase IA employed a 3+3 design to determine the MTD of buparlisib daily plus fulvestrant. Subsequent cohorts evaluated intermittent (5 of 7 day dosing) and continuous buparlisib (100mg daily). No more than 3 prior systemic treatments in the metastatic setting were allowed in Phase IB and Cohort C. Thirty one patients were enrolled. MTD was defined as buparlisib 100mg daily plus fulvestrant. Common adverse events (AEs) included fatigue (38.7 %), transaminases elevation (35.5 %), rash (29%), and diarrhea (19.4%). C-peptide was significantly increased during treatment, consistent with on-target effect of buparlisib. Compared to intermittent dosing, daily buparlisib was associated with more frequent early onset AEs and higher buparlisib ...

The Lancet. Oncology, Jan 27, 2015

Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). ... more Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL. Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude…

Journal of Clinical Oncology, 2009

Purpose To improve on current standards for breast cancer prognosis and prediction of chemotherap... more Purpose To improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit by developing a risk model that incorporates the gene expression–based “intrinsic” subtypes luminal A, luminal B, HER2-enriched, and basal-like. Methods A 50-gene subtype predictor was developed using microarray and quantitative reverse transcriptase polymerase chain reaction data from 189 prototype samples. Test sets from 761 patients (no systemic therapy) were evaluated for prognosis, and 133 patients were evaluated for prediction of pathologic complete response (pCR) to a taxane and anthracycline regimen. Results The intrinsic subtypes as discrete entities showed prognostic significance (P = 2.26E-12) and remained significant in multivariable analyses that incorporated standard parameters (estrogen receptor status, histologic grade, tumor size, and node status). A prognostic model for node-negative breast cancer was built using intrinsic subtype and clinical information. The...

The New England journal of medicine, Jan 22, 2012

Background The myelodysplastic syndromes are a group of hematologic disorders that often evolve i... more Background The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood. Methods We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations. Results Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardle...

Clinical Cancer Research, 2014

Purpose: Improved understanding of the molecular basis underlying oral squamous cell carcinoma (O... more Purpose: Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance. Experimental Design: Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes, and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature, and we assessed its representation in four independent human datasets comprising 324 patients using weighted voting and gene set enrichment analysis. Kaplan–Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A quantitative real-time PCR assay based on the mouse signature coupled to a machine-learning algorithm was dev...

The Cancer Genome Atlas Research Network* Adenocarcinoma of the lung is the leading cause of canc... more The Cancer Genome Atlas Research Network* Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Cell reports, Jan 21, 2018

Herein, we report an oral cavity squamous cell carcinoma (OCSCC) patient-derived xenograft (PDX) ... more Herein, we report an oral cavity squamous cell carcinoma (OCSCC) patient-derived xenograft (PDX) platform, with genomic annotation useful for co-clinical trial and mechanistic studies. Genomic analysis included whole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) on 16 tumors and matched PDXs and additional whole-genome sequencing (WGS) on 9 of these pairs as a representative subset of a larger OCSCC PDX repository (n = 63). In 12 models with high purity, more than 90% of variants detected in the tumor were retained in the matched PDX. The genomic landscape across these PDXs reflected OCSCC molecular heterogeneity, including previously described basal, mesenchymal, and classical molecular subtypes. To demonstrate the integration of PDXs into a clinical trial framework, we show that pharmacological intervention in PDXs parallels clinical response and extends patient data. Together, these data describe a repository of OCSCC-specific PDXs and illustrate conservation of p...

Nature Communications, 2018

Nature communications, Sep 4, 2018

Here we report targeted sequencing of 83 genes using DNA from primary breast cancer samples from ... more Here we report targeted sequencing of 83 genes using DNA from primary breast cancer samples from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients to determine interactions between somatic mutation and prognosis. Independent validation of prognostic interactions was achieved using data from the METABRIC study. Previously established associations between MAP3K1 and PIK3CA mutations with luminal A status/favorable prognosis and TP53 mutations with Luminal B/non-luminal tumors/poor prognosis were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutations were also a poor outcome driver that was validated in METABRIC. For MA12, poor outcome associated with PIK3R1 mutation was also reproducible. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false discovery correction (q = 0.0003). In conclusion, uncommon recurrent somatic mutations should ...

Nature communications, Sep 17, 2018

Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant dis... more Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results sug...