Mardis, Elaine R.

Abstract Glioblastoma is a highly lethal malignancy with dismal overall survival and near universal recurrence despite maximal multimodal therapy. Patients with unmethylated O6-methylguanine methyltransferase (MGMT) promoters do not derive survival benefit from adjuvant temozolomide. Immunotherapies have revolutionized cancer care; however, this modality has yet to translate into survival benefits in glioblastoma in part due to both local and systemic immunosuppressive states. Here, we report the results of a phase 1 clinical trial (NCT04015700) evaluating the safety and feasibility of GNOS-PV01, a personalized DNA vaccination platform that safely immunized against up to 40 patient-specific neoantigens in a clinically relevant timescale following surgical resection and radiation for MGMT-unmethylated glioblastoma patients. Multisector tumor sampling at time of resection enabled personalized and spatially representative neoantigen identification through an established pipeline. In the nine participants receiving vaccines, there were no unexpected toxicities or serious adverse events with a median vaccine delivery time of 10 weeks post-radiation. The vaccination was strongly immunogenic and induced activation and expansion of both local infiltrating CD8+ and CD4+ T-cells and circulating peripheral T-cells. T-cell receptor sequencing revealed both expanded pre-existing populations as well as novel neoantigen-specific populations, suggesting that vaccination both reinvigorates pre-existing immunity and generates novel immune reactivity. We developed a new technology to profile T-cells at single-nuclei resolution from frozen tissue revealing that vaccination altered gene expression signatures involved in inflammatory response and lymphocyte activation in the tumor microenvironment. Exposure to dexamethasone greatly suppressed immune reactivity, while PD-1 blockade enhanced local immune responses. With respect to efficacy, one third of patients survived longer than 24 months with one long-term survivor living >40 months from time of diagnosis, exceeding survival of recently published trials. Thus, our study demonstrates the safety, feasibility, and preliminary clinical efficacy of a personalized multivalent neoantigen vaccination platform in a devastating cancer.

Abstract CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

Abstract Patients with metastatic breast cancer (MBC) typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is in part due to molecular features including increased tumor cell clonal heterogeneity, multiple drug resistance mechanisms, and alterations of the tumor microenvironment. The AURORA US Metastasis Project was established with the goal to identify molecular features specifically associated with metastasis. We therefore collected and molecularly characterized specimens from 55 metastatic breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtypes. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. We further found evidence for ER-mediated downregulation of genes involved in cell-cell adhesion in metastases. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in B cells and T cells. In 17% of metastatic tumors, we identified DNA hypermethylation and/or focal DNA deletions near HLA-A that were associated with its’ significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some patients with MBC.

Abstract Background: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. Methods: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer–specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer–specific mortality, and somatic mutations. Results: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer–specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07–3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer–specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. Conclusions: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer–specific mortality and specific somatic mutated genes. Impact: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.

Abstract Background: It has become increasingly clear that effective treatment of metastatic breast cancer (MBC) requires an in-depth understanding of the molecular differences between primary tumors and metastases. The AURORA US Network was established to collect primary breast cancer-metastasis pairs for multi-platform genomic profiling in order to identify the molecular drivers of metastatic disease. AURORA US has both a retrospective and prospective phase. This is the first report of the retrospective phase. Methods: Archived tissue samples from the primary tumor and at least one distant metastasis were retrospectively collected from 83 MBC patients. Following internal quality assessment, samples from 55 pts, including 105 distinct metastatic lesions, were subject to DNA low pass whole genome and exome sequencing, DNA methylation arrays, and RNA sequencing. Early analyses of these multi-platform data include: DNA methylation, tumor gene expression and microenvironmental signatures, somatic and germline variants, DNA copy number changes, and structural variants between breast primaries and matched metastases. Results: Median age at diagnosis was 49 years (25-76); 32 (58%) were Stage I or II at presentation, 27 (49%) had a family history of breast cancer, and 20 (36%) had a second breast primary. Median disease-free interval before developing MBC was 2 years (range 0-36, 5 patients presented with Stage IV). Median overall survival from initial presentation was 4 years (range 0-37). Median survival after developing MBC was 1 year (range 0-13), with a median of three treatments. Primary tissue samples were banked from 1977-2017 and metastases were banked from 1999-2017. Clinical phenotypes of the primaries included 27 HR+ (49%), 15 triple negative (TNBC, 27%), and 11 HER2+ (20%, 12 missing HER2 status). Intrinsic subtype distribution of the primaries included 17 Basal-like (31%), 17 Luminal A (31%), 7 Normal-like (13%), 5 HER2-enriched (9%), and 1 Luminal B, with 8 pending. All metastases from the Basal-like cases remained Basal-like, while metastases from luminal primaries tended to gain HER2-Enriched subtype features (5/18, p = 0.01). Overall, we identified significant metastasis-enriched alterations in metabolism pathways, an increase in proliferation, and the loss of differentiation signatures and immune infiltrates with progression; the latter being the most pronounced in brain metastases. The most frequent somatic mutations in this cohort were in TP53, NCOR1, and RUNX1. Interestingly, ERBB2, EGFR, and ATM were also mutated in ≥10% of the tumors sequenced. In almost all cases, CpG island hypermethylation was clonally present in the primary tumor and persisted stably in the majority of metastatic lesions. Promoter CpG island hypermethylation was also identified in some metastatic lesions at JAM3, an important cellular adhesion molecule,and this was accompanied by reduced mRNA expression. CONCLUSIONS: Collection of banked primary and metastatic tissue pairs identified a young MBC cohort with a high frequency of breast cancer family history and second breast primaries. Molecular characterization of luminal tumor pairs highlighted acquisition of aggressive traits including increased proliferation and loss of differentiation in the metastases. In contrast, basal-like pairs remained relatively unchanged, except for the loss of immune activation. Ongoing analyses to be presented include clonal heterogeneity and phylogeny, novel metastasis signature discovery, gene fusion, and endogenous retrovirus detection. Citation Format: Tari A King, Minetta C Liu, Marni B McClure, Toshinori Hinoue, Benjamin J Kelly, Chad J Creighton, Jay Bowen, Kristen Leraas, Robyn T Burns, Sara Coppens, Salma Rezk, Amy L Garrett, Justin M Balko, Joel S Parker, Ben H Park, Ian Krop, Carey Anders, Katherine A Hoadley, Julie Gastier-Foster, Mothaffar F Rimawi, Rita Nanda, Nancy U Lin, Claudine Isaacs, P. Kelly Marcom, Anna Maria Storniolo, Fergus J Couch, Elaine R Mardis, Adrian V Lee, Uma Chandran, Peter W Laird, Susan G Hilsenbeck, Larry Norton, Andrea L Richardson, W. Fraser Symmans, Lisa A Carey, Antonio C Wolff, Nancy E Davidson, Charles M Perou, the AURORA US Network. Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS3-08.

503 Background: To correlate clinical features of estrogen receptor positive breast cancer with somatic mutations, massively parallel sequencing (MPS) was applied to tumor and normal DNAs accrued from patients treated with neoadjuvant aromatase inhibitors (AI). Methods: MPS was applied to 77 baseline tumor biopsy samples from the preoperative letrozole trial (JACS 2009: 208, 906) and the Z1031 trial (JCO 2011: 29, 2342) followed by targeted sequencing in another 240 trial samples. Standard statistical approaches were used to compare mutation status and clinical parameters and pathway-based correlation was used to assess interactions between signaling perturbations induced by gene mutations and response to neoadjuvant AI. Results: Eighteen genes were significantly mutated above background. Aside from PIK3CA mutations, the list is dominated by loss-of-function mutations in tumor suppressor genes. Five (RUNX1, CBFP, MYH9, MLL3 and SF3B1) have been previously linked to benign and malignant hematopoietic disorders. Clinical correlation revealed that TP53 mutation was associated with PAM50 LumB status, high-grade histology and high proliferation rates whereas loss-of-function mutations in MAP3K1 associate with PAM50 lumA status, low proliferation rates, and low grade histology. Mutations in GATA3 were associated with greater suppression of proliferation upon AI treatment suggesting mutGATA3 may predict endocrine response. Notably, mutations in MAP3K1 were more common in PIK3CA mutant cases, suggesting cooperation. Pathway analysis demonstrated that rare MAP2K4 mutations produce similar pathway perturbations as MAP3K1 mutation, a logical finding since MAP2K4 is a substrate for MAP3K1. Signaling network patterns driven by lncRNA MALAT1 mutations were associated with multiple poor clinical outcome features. Rare mutations in druggable kinases included two in the kinase domain of HER2. Conclusions: Tumor heterogeneity in luminal-type breast cancer is driven by specific patterns of somatic mutations, however most druggable or potentially prognostic mutations are infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing approaches and large scale investigations.

Abstract Background: Multiple myeloma (MM) is a hematologic cancer characterized by a diversity of genetic lesions-translocations, copy number alterations (CNAs), and single nucleotide variants (SNVs). The prognostic value of translocations and of CNAs has been well established. Determining the clinical significance of SNVs, which are recurrently mutated at much lower frequencies, and how this significance is impacted by translocations and CNAs requires additional, large-scale correlative studies. Such studies can be facilitated by cost-effective targeted sequencing approaches. Hence, we designed a single-platform targeted sequencing approach capable of detecting all three variant types. Methods: We designed oligonucleotide probes complementary to the coding regions of 467 genes and to the IgH and MYC loci, allowing a probe to closely match at most 5 regions within the genome. Genes were selected if they were expressed in an independent RNA-seq MM data set and harbored germline SNP-filtered variants that: (1) occurred with frequency >3%, (2) were clustered in hotspots, (3) occurred in recurrently mutated "cancer genes" (as annotated in COSMIC or MutSig), or (4) occurred in genes involved in DNA repair and/or B-cell biology. IgH and MYC tiling was unbiased (with respect to annotated features within the loci) and spanned from 50 kilobasepairs (kbps) upstream of both regions to 50 kbps downstream of IgH and 100 kbps downstream of MYC. Results: We performed targeted sequencing of 96 CD138-enriched samples derived from MM patients, as well as matched peripheral blood leukocyte normal controls. Sequencing depth (mean 107X) was commensurate with that of available exome sequencing data from these samples (mean 71X). Samples harbored a mean of 25 non-silent variants, including those in known MM-associated genes: NRAS (24%), KRAS (22%), FAM46C (17%), TP53 (10%), DIS3 (8%), and BRAF (3%). Variants detected by both platforms showed a strong correlation (r^2 = 0.8). The capture array detected activating, oncogenic variants in NRAS Q61K (n=3 patients) and KRAS G12C/D/R/V (n=5) that were not detected in exome data. Additionally, we found non-silent, capture-specific variants in MTOR (3%) and in two transcription-related genes that have been previously implicated in cancer: ZFHX4 (5%) and CHD3 (5%). To assess the potential role of deep subclonal variants and our ability to detect them, we performed additional sequencing (mean 565X) on six of the tumor/normal pairs. This revealed 14 manually-reviewed, non-silent variants that were not detected by the initial targeted sequencing. These had a mean variant allele frequency of 2.8% and included mutations in DNMT3A and FAM46C. At least one of these 14 variants occurred in five of the six re-sequenced samples. This highlights the importance of this additional depth, which will be used in future studies. Our approach successfully detected CNAs near expected frequencies, including hyperdiploidy (52%), del(13) (43%), and gain of 1q (35%). Similarly, it inferred IgH translocations at expected frequencies: t(4;14) (14%), t(6;14) (3%), t(11;14) (15%), and t(14;20) (1%). As expected, translocations occur predominantly within the IgH constant region, but also frequently 5' (i.e., telomeric) of the IGHM switch region, and occasionally within the V and D regions. We detected MYC -associated translocations, whose frequencies have been the subject of debate, at 10% (n=9 patients), with five involving IgH, three having both partners in or near MYC, and one having both types. Finally, our platform detected novel IgH translocations with partners near DERL3 (n=2), MYCN (n=1), and FLT3 (n=1). Additional evidence suggests that DERL3 and MYCN may be targets of IgH-induced overexpression: of 84 RNA-seq patient samples, six exhibited outlying expression of DERL3, including one sample in which we detected the translocation in corresponding DNA, and one exhibited outlying expression of MYCN. Conclusion: Our MM-specific targeted sequencing strategy is capable of detecting deeply subclonal SNVs, in addition to CNAs and IgH and MYC translocations. Though additional validation is required, particularly with respect to translocation detection, we anticipate that such technology will soon enable clinical testing on a single sequencing platform. Disclosures Vij: Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy; Takeda, Onyx: Research Funding.

Abstract 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 preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.

Abstract The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the Colorectal Cancer Family Registry (CCFR) aims to identify genetic variants and environmental risk factors that impact colorectal cancer (CRC). Over 30 studies from North America, Europe, and Australia participate in GECCO. These studies have collected clinical, epidemiological, and survival data, as well as blood and tumor biospecimens, for over 80,000 CRC cases and controls. The current study aims to conduct targeted deep sequencing of tumors and matching normal DNA to identify recurrent and novel somatic and germline variants in 4,200 CRC cases. To achieve this goal, an AmpliSeq targeted sequencing panel of 1.12 Mbp was constructed to sequence the coding regions of 190 significantly mutated genes identified from whole exome sequencing datasets generated by the Nurses’ Health Study and Health Professional’s Follow-up Study, and The Cancer Genome Atlas. The panel also covers coding regions of 15 genes with germline high penetrance mutations in CRC, 54 regions to detect CRC-related copy number alterations (CNAs), and microsatellite and homopolymer repeat regions to identify defective DNA mismatch repair. Primers were also included to detect Fusobacterium nucleatum DNA in tumor biopsies, as F. nucleatum is thought to promote CRC carcinogenesis. Sequencing of the DNA libraries on Illumina HiSeq 2500 produced a mean coverage of greater than 500X for tumor DNA and 100X for normal DNA, with >85% of the bases covered at the target at 50x. So far, targeted sequencing of >1,500 DNA samples from CRC tumors and normal tissues has identified recurrent and novel somatic mutations, germline genetic variants, and hypermutation status of the tumors due to defective DNA mismatch repair or pathogenic mutations in the POLE gene. Targeted sequencing has also allowed quantification of the F. nucleatum DNA in tumor biopsies; the results were validated by a multiplex QPCR assay. At the AACR annual meeting, we will present targeted sequencing results generated from the first two GECCO-participating studies (n=1,300 cases). These data will be valuable for future association testing of somatic mutations, CNAs, hypermutation status, and F. nucleatum with germline genetic variants, lifestyle, and environmental risk factors and survival. This large study will allow development of better strategies for diagnosis, treatment, and prevention of CRC. Citation Format: Syed H. Zaidi, Wei Sun, Jeroen Huyghe, Catherine S. Grasso, Quang Trinh, Charles Connolly, Amy French, Jasmine Mu, Marios Giannakis, Eve Shinbrot, Ivan Borozan, Michael J. Quist, Hermann Brenner, Daniel Buchanan, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Vincent Ferretti, Charles Fuchs, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Wen-Yi Huang, Paul Krzyzanowski, Stephen Lee, Mathieu Lemire, Jessica Miller, Danielle Pasternack, Cherie Teney, Elaine Mardis, Polly Newcomb, Lincoln Stein, Lee Timms, David Wheeler, Christina Yung, Niha Zubair, Levi Garraway, Shuji Ogino, Li Hsu, Steven Gallinger, Stephen Thibodeau, Thomas Hudson, Ulrike Peters. Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1286. doi:10.1158/1538-7445.AM2017-1286

Abstract The completion of The Cancer Genome Atlas (TCGA) project for colorectal cancer (CRC) has enabled a new, focused phase of sequencing tumor samples for which genome-wide genetic, epidemiological, clinical and lifestyle data have been collected. By combining somatic mutational profiles with these aforementioned data, we may identify and report effective prevention and treatment approaches for a broader population of individuals. The advent of targeted deep sequencing approaches using DNA obtained from formalin fixed paraffin embedded tissues has made possible the genetic characterization of the large numbers of patients needed to make such an effort relevant. As a first step, we describe a custom gene panel designed from large-scale studies for targeted deep sequencing, and its application to over 4,200 CR tumors, collected by the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). This study is designed to identify recurrent somatic mutations and copy number alterations (CNAs) for association testing with germline genetic and lifestyle and environmental risk factors for CRC, and thereby identify relevant approaches to impact cancer prevention. The targeted CRC panel includes 205 genes. Genes were primarily selected as significantly mutated genes identified from the Nurses’ Health Study and Health Professional's Follow-up Study (n = 700), and TCGA (n = 525). We also included 15 genes associated with high penetrance germline mutations and augmented the list to include genes in pathways of somatically altered genes, identified by literature review, from public databases and known to be associated with loss of heterozygosity. For these 205 genes, amplification primers were designed to include all coding regions of transcripts that are listed in the UCSC Genome Browser. For regions with CNAs, the TCGA dataset was analyzed to include regions with greater than or equal to 2 copy focal gains or losses that were found in more than 4 or 3 tumors, respectively. Candidate genes in regions with significant CNAs from the TCGA CRC publication (Nature 2012) were also included. For CNAs, 6 to 12 amplicons were designed for each of the 56 selected regions (32 gains and 24 losses). Additional target regions include: 1) 25 microsatellite loci previously used to identify defective DNA mismatch repair and 212 homoploymer repeats. These include microsatellite loci recommended by the NCI Consensus Panel for identifying MSI; 2) amelogenin (for gender); and 3) Fusobacterium to detect a putative CRC-associated pathogen in tumor biopsies. At the AACR annual meeting, we expect to present results for deep sequencing (∼1,000X) of the first 1,000 CR tumors, including any preliminarily identified pathways and subtypes that may provide the basis for association testing with germline genetic and lifestyle and environmental risk factors needed for inferring better approaches to prevention and treatment of CRC. Citation Format: Syed H. Zaidi, Catie Grasso, Jasmine Mu, Eve Shinbrot, Marios Giannakis, Charles Connolly, Ivan Borozan, Hermann Brenner, Peter Campbell, Andrew Chan, Jenny Chang-Claude, Mengmeng Du, Vincent Ferretti, Amy French, Charles Fuchs, Steven Gallinger, Levi Garraway, Andrea Gsur, Marc Gunter, Tabitha Harrison, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen Huyghe, Mathieu Lemire, Elaine Mardis, John McPherson, Polly Newcomb, Lincoln Stein, Wei Sun, Lee Timms, Quang Trinh, David Wheeler, Christina Yung, Niha Zubair, Shuji Ogino, Stephen Thibodeau, Ulrike Peters, Thomas Hudson. Linking the molecular profile of colorectal tumors to germline genetic and environmental risk factors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5221.