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• Genomic landscape of oral cancers (Illumina RNA-Seq)

  Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

  Study EGAS00001003237

• Genomic landscape of oral cancers (Complete Genomics WGS)

  Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

  Study EGAS00001002393

• Genome wide association study on coronary heart disease in patients with familial hypercholesterolemia

  Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap 550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (p<1×10-4). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an ‘extreme genetics’ approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may therefore not lead to significant gains in statistical power. (NB submitten and conditionally accepted at European Journal of Human Genetics-please use abstract only for internal review until submission complete)

  Study EGAS00001000734

• Pharmacological and genomic profiling identifies NFκB-targeted treatment strategies for mantle cell lymphoma

  Mantle cell lymphoma (MCL) is an aggressive malignancy characterized by poor prognosis, underscoring the need for novel therapeutic strategies1. In this study, we employed large-scale pharmacological profiling of 16 pathway inhibitors across more than 100 hematological cell line models to identify novel therapeutic approaches. This screen identified a subset of MCL cell lines that were highly sensitive to the B-cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin (STN), which are currently in clinical trials2, 3. Sensitive MCL models exhibited chronic activation of the CARD11-BCL10-MALT1 (CBM) complex and dependency on downstream classical NFκB signaling. In contrast, insensitive cell lines displayed activation of the alternative NFκB pathway. Massively parallel transcriptome sequencing identified mutations in negative regulators of the alternative NFκB pathway in ibrutinib-insensitive cell lines. Notably, sequencing of 165 MCL patient samples revealed that components of the alternative NFκB pathway, particularly TRAF2 and BIRC3, are mutated in roughly 15% of MCL patients. Functional analyses of patient-derived BIRC3 mutant alleles indicated that these are loss-of-function mutants that constitutively activate alternative NFκB signaling. While being associated with insensitivity to ibrutinib, genetic lesions in the alternative pathway conferred dependence on NIK, a kinase that mediates signaling downstream of the TRAF2/3-BIRC2/3 complex. Thus, NIK represents a novel therapeutic target for MCL treatment, particularly for tumors refractory to BCR pathway inhibitors. Collectively, these findings reveal a pattern of mutually exclusive activation of the CBM-NFκB or alternative NIK-NFκB pathways in MCL and provide critical insights into patient stratification strategies for NFκB-pathway targeted agents.

  Study EGAS00001000622

• Whole exome sequencing of small cell neuroendocrine cancer of the cervix

  In order to improve treatment selection for high grade neuroendocrine carcinomas of the cervix (NECC), we performed a comparative genomic analysis between this rare tumor type and other cervical cancer types, as well as extra-cervical neuroendocrine small cell carcinomas of the lung and bladder. We performed whole exome sequencing on fresh-frozen tissue from 15 NECCs and matched normal tissue. We then identified mutations and copy number variants using standard analysis pipelines. Published mutation tables from cervical cancers and extra-cervical small cell carcinomas were used for comparative analysis. Descriptive statistical methods were used and a two-sided threshold of P < .05 was used for significance. In the NECC cohort, we detected a median of 1.7 somatic mutations per megabase (range 1.0-20.9). PIK3CA p.E545K mutations were the most frequency observed oncogenic mutation (4/15 tumors, 27%). Activating MAPK pathway mutations in KRAS (p.G12D) and GNAS (p.R201C) co-occurred in two tumors (13%). In total we identified PI3-kinase or MAPK pathway activating mutations in 67% of NECC. When compared to NECC, lung and bladder small cell carcinomas exhibited a statistically significant higher rate of coding mutations (P < .001 for lung; P = .001 for bladder). Mutation of TP53 was uncommon in NECC (13%) and was more frequent in both lung (103 of 110 tumors [94%], P < .001) and bladder (18 of 19 tumors [95%], P < .001) small cell carcinoma. These comparative genomics data suggest that NECC may be genetically more similar to common cervical cancer subtypes than to extra-cervical small cell neuroendocrine carcinomas of the lung and bladder. These results may have implications for the selection of cytotoxic and targeted therapy regimens for this rare disease.

  Study EGAS00001003142

• We evaluate the potential for routine WGS using ONT by sequencing the well-characterised reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome accompanied by severe immune dysregulation.

  Whole-genome sequencing (WGS) is becoming widely used in clinical medicine in diagnostic contexts and to inform treatment choice. While current sequencing technologies have been extremely successful, their reliance on short read lengths necessarily involves some limitations: accurately assaying certain genomic regions and classes of variation can be problematic. Recent advances in throughput and cost have made WGS using the Oxford Nanopore Technologies (ONT) MinION long-read single-molecule sequencer a potential solution to these challenges. Here we evaluate the potential for routine WGS using ONT by sequencing the well-characterised reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome accompanied by severe immune dysregulation, to 82× and 30× respectively. For NA12878, we evaluated single-nucleotide variant (SNV) calls based on data from multiple base-calling algorithms. We demonstrate that phasing metrics from a novel, reference panel-free, long-read-based method can improve variant-calling performance from otherwise modest levels, resulting in a false discovery rate of 7.1% and false negative rate of 8.5%; remaining errors are concentrated near homopolymers and in regions of reduced sequencing coverage. In the clinical sample, we are able to identify and directly phase two non-synonymous de novo variants in SAMD9L, (OMIM #159550) inferring that they both lie on a common paternal haplotype by overlap with parental genotypes at nearby common variants. This work demonstrates that methodological innovation can substantially reduce variant-calling error rates in ONT data, and that with on-going improvements in throughput, base-calling and dedicated long-read-based SNV-calling methodology, ONT offers promise as an option for clinical WGS.

  Study EGAS00001003469

• Prenatal lead exposure is associated with decreased cord blood DNA methylation of the glycoprotein VI gene involved in platelet activation and thrombus formation

  Early-life lead exposure impairs neurodevelopment and later exposure affects the cardiovascular system. Lead has been associated with reduced global 5-methylcytosine DNA methylation, suggesting that lead toxicity acts through epigenetic mechanisms. The objective of this study is to clarify how early life lead exposure alters DNA methylation of specific genes, using an epigenomic approach. We measured lead concentrations in urine (gestational week, GW, 8) and erythrocytes (GW 14), using ICP-MS, for 127 pregnant mothers recruited in the MINIMat food and supplementation cohort in rural Bangladesh. Cord blood DNA methylation was analyzed with the Infinium HumanMethylation450K BeadChip and top sites were validated by methylation-sensitive high-resolution melt curve analysis. Maternal urinary lead concentrations (divided into quartiles) showed significant (after adjustment for FDR) inverse associations with methylation at nine CpGs. Three of these sites were in the 5’ end, including the promoter, of glycoprotein IV (GP6); cg18355337 (q=0.029, β=-0.30), cg25818583 (q=0.041, β=-0.18) and cg23796967 (q=0.047, β=-0.17). The methylation in another CpG site in GP6 was close to significant (cg05374025, q=0.057, β=-0.23). The erythrocyte lead concentrations (divided into quartiles) were also inversely associated with CpG methylation in GP6, although this was not statistically significant after FDR-adjustments. Eight CpG sites in GP6 constituted a differentially methylated region in relation to urinary lead (p=0.005, q=0.48) and erythrocyte lead (p=0.007, q=0.46). In conclusion, we found that moderate prenatal lead exposure appear to epigenetically affect GP6, a key component of platelet aggregation and thrombus formation, suggesting a novel link between early lead exposure and cardiovascular disease later in life.

  Study EGAS00001001575

• Breast cancer women lack normal lifelong immune response after full-term pregnancies

  Immunological tolerance during pregnancy is necessary for women’s bodies to accept the semi-allogenic fetus. Interestingly, “immune evasion”, which consists of some similar immunological changes, was recently proposed as a hallmark of cancer. Looking at these results, it seems paradoxical that increasing number of full-term pregnancies (FTP) reduces the risk of breast cancer in women. Our aim was to use a systems epidemiology approach to investigate this paradox by modelling breast cancer incidence as a function of parity in the Norwegian Women and Cancer (NOWAC) cohort, then testing the mathematical model using gene expression from blood in a subcohort of these women: the NOWAC postgenome cohort. Lastly, we undertook a gene set enrichment analysis for immunological gene sets. A linear trend nicely fitted the dataset showing an 8% decrease in risk for each FTP, independent of stratification on other risk factors and lasting for decades after a woman’s last FTP. However, when we looked at gene expression we found that hundreds of genes showed linear trends in cancer-free controls, but this was not the case in /any/ of the samples from breast cancer cases. In the gene set enrichment analysis, samples consisted of human blood or cord blood and mouse bone marrow or spleen. We found more adaptive gene sets than expected in humans and more innate gene sets than expected in mice. None of the gene sets provided information about the long-term effects of immunological tolerance during pregnancy, but the lack of relevant reductionist experiments hampers our interpretation. We suggest that, after resolution at birth, the immunological tolerance induced by pregnancy augments immune response to cancer development.

  Study EGAS00001002616

• Accurate detection and classification of pediatric sarcomas based on cell-free DNA fragmentation patterns

  Sequencing of cell-free DNA in the blood of cancer patients (“liquid biopsy”) provides attractive opportunities not only for early diagnosis, but also for minimally invasive monitoring of treatment response and disease courses. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we developed an integrated genetic/epigenetic analysis method and applied it to 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. We achieved sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. We evaluated different metrics for cell-free DNA fragmentation analysis and developed LIQUORICE, a bioinformatic tool for detecting circulating tumor DNA based on tumor-specific chromatin structure. Using machine learning methods, we combined several fragmentation-based metrics into an integrated approach for liquid biopsy analysis tailored to cancers with low mutation rates but widespread epigenetic deregulation. Clinical associations highlighted the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. Additionally, we performed low coverage whole-genome-sequencing on 43 tumor biopsy samples from patients with Ewing sarcoma, in order to compare copy number aberrations detected in cell-free DNA and biopsy samples of the same patients. For validation of the epigenetic signatures inferred from cell-free DNA, we further performed reduced representation bisulfite sequencing (RRBS) on 38 matched biopsy samples from patients with Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent somatic mutations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.

  Study EGAS00001005127

• Spiradenocarcinoma

  • Spiradenocarcinoma is a rare cutaneous sweat gland adnexal cancer with potential for aggressive behaviour. They are classified histologically into low- and high-grade tumours, with morphologically low-grade tumours thought to behave more favourably. However, limited information is available, with only 18 published cases. • We have collected morphologically low-grade spiroadenocarcinomas (one with a lung metastasis) and high-grade spiroadenocarcinomas, as well as some spiradenomas (benign lesions), cylindromas (another type of malignant cutaneous sweat gland adnexal tumour) and hybrid spiradenoma-cylindromas. • H&E-stained sections were reviewed, follow-up was obtained, and immunohistochemistry for Ki-67, p53 and, MYB has been performed. The tumours were solitary, measuring 0.8-7?cm (median: 2.7?cm), with a predilection for the head and neck of elderly patients (median age: 72 years; range 53-92) without gender bias. Histologically, the tumours were multinodular and located in deep dermis and subcutis. A pre-existing spiradenoma was present in all cases. The malignant component was characterized by expansile growth with loss of the dual cell population, up to moderate cytological atypia and increased mitotic activity (median: 10/10 HPF; range 1-28). Additional findings included squamoid differentiation (n=9), necrosis (n=7), and ulceration (n=5). P53 expression was variable and no significant differences were noted in the benign compared with the malignant parts of the tumours. In contrast, in the malignant components the Ki-67 proliferative index was slightly increased, and MYB expression was lost. Follow-up (median: 67 months; range: 13-132) available for 16 patients (84%) revealed a local recurrence rate of 19% but no metastases or disease-related mortality. • Here we wish to exome sequence these cases to define the first genomic landscape for this malignancy.

  Study EGAS00001001799