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• Identifying New Genetic Subtypes in Follicular Lymphoma

  Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and was associated with a lower proliferative history compared to the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Collectively, our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

  Study EGAS50000000435

• Genomic Profiling Reveals Spatial Intra-tumour Heterogeneity in Follicular Lymphoma

  Follicular lymphoma (FL) is an incurable indolent non-Hodgkin’s lymphoma (NHL) that behaves heterogeneously and is synonymous with the reciprocal translocation t(14;18)(q32;q21), leading to aberrant constitutive over-expression of BCL2 [ref]. High risk groups with poor overall survival include patients that transform to a high grade lymphoma, most commonly diffuse large B cell lymphoma (DLBCL) or progress early (within 2 years) of receiving treatment. Recently several studies have shed light on the diverse genomic landscape of FL, with frequently mutated genes including those involved in chromatin remodelling, (CREBBP, KMT2D, EZH2, EP300), immune modulation (TNFRSF14), JAK-STAT (STAT6, SOCS1), NF-ĸB (CARD11, MYD88, TNFAIP3) and mTORC1 signalling (RRAGC) [ref]. To date, the majority of these studies have either focussed on inter-patient genetic heterogeneity or established the extent of clonal heterogeneity as a patient’s tumour evolves over time. Furthermore, these temporal studies have alluded to the existence of a tumour-repopulating population (referred to as the common progenitor cell (CPC)) that evades treatment and acts as a reservoir, seeding each subsequent relapse and transformation event. Although these previous studies have illuminated the longitudinal clonal dynamics that occur in FL, our understanding of the degree of spatial or intra-tumour heterogeneity (ITH) that exists within an individual patient thus far remains limited. Earlier studies have predominantly focused on differences in cytological grade and immunophenotype between spatially separated lymph nodes and bone marrow, the most common site of extra-nodal involvement in FL, with genomic profiling restricted to examining somatic hypermutation patterns in IgVH genes [ref]. In contrast next generation sequencing has been increasingly utilised in solid organ malignancies to derive comprehensive genomic profiles from spatially separated sites. The seminal study by Gerlinger et al revealed profound differences in the genetic make-up between individual primary and metastatic sites of renal cell carcinoma [ref]. Significant heterogeneity has since been demonstrated both between and within lesions in the same patient in lung, pancreas and breast cancer with presumed driver mutations distributed within the “branches” of the evolutionary phylogenetic tree, suggesting that a single biopsy is incapable of capturing the full genomic heterogeneity of an individual’s malignancy [ref]. This geographical heterogeneity not only adds to the diverse pool of tumour subclones that may contribute to drug resistance mechanisms but importantly, presents a major obstacle for precision-based approaches focussed on targeting specific lesions within a single biopsy. In FL, the exponential increase in clinical trials using novel agents such as EZH2, PI3K and BTK inhibitors reflects this shift in cancer care and along with the development of molecular prognostic scores such as the m7-FLIPI highlights the clinical need to accurately define genomic alterations with clinical relevance. As the majority of FL patients manifest disseminated tumour involvement, we sought to uncover the extent and clinical importance of spatial heterogeneity in FL by comprehensively genetically profiling 22 synchronously removed spatially separated biopsies from 9 patients. Using a combination of whole exome and targeted deep sequencing, our results inferred the complex subclonal architecture within these tumours and the mutational differences between anatomical sites, demonstrating cases with significant intrinsic genetic diversity.

  Study EGAS00001002492

• Sensitive and robust liquid biopsy-based detection of PIK3CA mutations

  Over the last years, the treatment of hormone receptor-positive metastatic breast cancer patients has dramatically changed. Combination strategies attempting to overcome resistance to endocrine therapy such as targeting the PI3 kinase pathway are gaining importance. The phase III SOLAR-1 trial demonstrated the benefit of the addition of alpelisib to fulvestrant, thereby providing further clinical evidence of the increasing importance of PIK3CA testing. Here, we performed a comparison of liquid biopsy and tissue-based detection of PIK3CA mutations in HR-positive metastatic breast cancer patients. Plasma samples and the latest available tumor tissue from 69 patients with metastatic hormone-receptor positive breast cancer were analyzed for PIK3CA hotspot mutations. A high-resolution NGS assay (SiMSen-Seq) was used for plasma samples covering 11 recurrent PIK3CA mutations, used for stratification in SOLAR-1. Additionally, mFAST-SeqS was used to estimate the tumor fractions in the plasma samples. For tumor tissue samples, targeted Ion Torrent NGS was employed. Matched tissue and plasma samples were available from 63 patients. PIK3CA mutations were detected in 46.1% of the tissue samples and in 50.7% of the plasma samples. The variant allele frequency (VAF) ranged from 4.36% to 72.93% with a median of 28.60% in tissue samples, and from 0.28% to 49.85% with a median of 1.17% in plasma samples. The most frequent variants in tissue and plasma were H1047R, E545K, and E542K. We detected at least one of 11 PIK3CA mutations from the SOLAR-1 trial in 51/63 patients, both in tissue and plasma. In 7 patients, such mutations were found only in plasma. In 5 patients, PIK3CA mutations found in tissue were not detectable in ctDNA, 2 of which had a low tumor fraction.Together, in 33/67 plasma samples without detectable PIK3CA mutations, 18 samples had elevated tumor fraction, implicating true negative results. In the remaining 15 patients with low tumor fraction, additional tissue analysis was needed. SiMSen-Seq-based detection of PIK3CA mutations in plasma shows advantageous concordance with the tissue analyses. A combination with an untargeted, mutation-independent approach for detecting ctDNA fractions may confirm a negative PIK3CA result and thereby enhance the performance of the SiMSen-Seq test. This combinatory approach for selecting suitable patients for alpelisib treatment should be validated in larger patient cohorts.

  Study EGAS00001004940

• Homozygous inactivation of CHEK2 is linked to a familial case of multiple primary lung cancer with accompanying cancers in other organs

  In clinical practice, there are a number of cancer patients with clear family histories, but not belonging to existing familial malignancies. Recent advances in genomic technologies have enhanced the possibility of identifying causative genes in such cases. Two siblings, an elder sister and a younger brother, were found to have multiple primary lung cancers at the age of 60. The former subsequently developed breast cancer, and had a history of myoma uteri. The latter had initially developed prostate cancer at the age of 59, and had a history of colon cancer. SNP genotyping revealed that approximately 10% of the genomes were homozygous in both patients. Exome sequencing revealed non-synonymous mutations in four genes in the runs of homozygosity: CHEK2, FCGRT, INPP5J, and SFI1. Evolutionary conservation of primary protein structures suggested the functional importance of the CHEK2 mutation, R474C. This mutation altered the tertiary structure of CHK2 by disrupting the salt bridge between R474 and E394. No such structural changes were observed with the other three mutated genes. Subsequent cell-based transfection analysis revealed that CHK2 R474C was unstable and scarcely activated. We concluded that CHEK2 is a causative gene in this case of familial cancer. Although homozygous inactivation of CHEK2 in mice led to cancers in multiple organs, accumulation of additional human cases is needed to establish its pathogenic role in humans.

  Study JGAS000057

• Identification of Modifiers of 22q11.2 Deletion Syndrome in Whole Genome Sequence - CIDR

  This project aims to identify genetic modifiers of congenital heart disease (CHD), which occurs among 22q11.2 deletion syndrome (22q11.2DS; also known as DiGeorge syndrome/velo-cardio-facial syndrome) patients. In contrast to the prevalence of ~0.8% in the general population, about 60%-70% of 22q11.2DS patients have CHD, of which most are conotruncal heart defects, making 22q11.2DS a very ideal model to study the genetic underpins of CHD. The chromosome 22q11.2 region is susceptible to meiotic chromosome rearrangements leading to hemizygous deletions, because there are large blocks of low copy repeats, termed LCR22s, that are dispersed in the region. Non-allelic homologous recombination during meiosis can lead to specific-sized deletions. Approximately 90% have a typical hemizygous 3 million base pair (Mb) deletion between LCR22-A and -D, while some have nested deletions between LCR22-A and B or LCR22-A and C. Our goal is to perform a case-control association study, in which cases have CHD, while controls have normal heart structures, all with 22q11.2DS. All individuals are unrelated and have been collected from collaborators in the US, Canada and Europe. All subjects received a clinical diagnosis of 22q11.2DS and signed informed consent to allow a blood sample to be collected for research. The DNA samples were de-identified in 2 steps to protect their privacy. We then determined deletion type using multiplex ligation-dependent probe amplification (MLPA). This information is provided for the great majority of subjects. We also obtained cardiac phenotype information from echocardiogram reports as well as reported race and ethnicity (Hispanic vs. non-Hispanic information), which is required for the analysis. We will obtain 30X whole-genome sequence data from NIH CIDR. We will first annotate the sequence variants identified to uncover rare ( For genotype data, we will provide the raw fastq data from whole-genome sequencing as well as the called variants file in a VCF file. For phenotype data, we will provide the sample relationship files (ped files), CHD affection status, deletion type, and race.

  Study phs002514

• Genomics of Substance Use Disorders in Latin American Populations

  This is a subsample of the National Survey of Drug, Alcohol, and Tobacco Use, administered in 2016 between August and October to participants aged 12-65 in urban and rural Mexican households, named Mexican Genomic Database for Addiction Research (MxGDAR). The objective of the survey was to evaluate the patterns of use of different psychoactive substances and mental health problems in Mexico. The sample universe was made up of primary sampling units (PSUs) that were the sum of basic statistical geographic areas, stratified by state and urban-rural communities. An adult aged 18-65 was chosen randomly from each household, and an adolescent aged 12-17 was also chosen randomly from the household which has at least one member under 18. The second administration of the survey included a subsample of 13,130 respondents who agreed to give a saliva sample for DNA analysis, to be used in analyzing the relationship of mental health, addiction, and genetics. This sample was weighted according to selection probability to be representative on the national level. Mental health symptomatology for these individuals was evaluated using the Diagnostic Interview for Psychosis and Affective Disorders (DI-PAD) using the operational criteria for psychotic disorders (OPCRIT v.4.0), administered by interviewers trained in its use. It includes the evaluation of symptomatology of psychosis, depression, anxiety, obsession/compulsion, mania/hypomania, and post-traumatic stress. The study seeks to replicate genetic associations with substance use (LINC01622), psychiatric disorders (PTPRM), or comorbidity between both (MGMT) reported in following paper: https://pubmed.ncbi.nlm.nih.gov/33762635/. Funding for genotyping was provided by the National Institute on Drug Abuse (NIDA), one of the National Institutes of Health (NIH).

  Study phs003558

• Targeted de-methylation of the FOXP3-TSDR

  CD4+ regulatory T cells (Tregs) are key mediators of immunological tolerance and promising effector cells for immuno-suppressive adoptive cellular therapy to fight autoimmunity and chronic inflammation. Their functional stability is critical for their clinical utility and has been correlated to the demethylated state of the TSDR/CNS2 enhancer element in the Treg lineage transcription factor FOXP3. However, proof for a causal contribution of the TSDR de-methylation to FOXP3 stability and Treg induction is so far lacking. We here established a powerful transient-transfection CRISPR-Cas9-based epigenetic-editing method for the selective de-methylation of the TSDR within the endogenous chromatin environment of a living cell. The induced de-methylated state was stable over weeks in clonal T cell proliferation cultures even after expression of the editing complex had ceased. Epigenetic editing of the TSDR resulted in FOXP3 expression, even in its physiological isoform distribution, proving a causal role for the de-methylated TSDR in FOXP3 regulation. However, successful FOXP3 induction was not associated with a switch towards a functional Treg phenotype, in contrast to what has been reported from FOXP3 overexpression approaches. Thus, TSDR de-methylation is required, but not sufficient for a stable Treg phenotype induction. Therefore, targeted demethylation of the TSDR may be a critical addition to published in vitro Treg induction protocols which so far lack FOXP3 stability.

  Study EGAS00001004867

• Inherited Genetic Variation and Predisposition to Testicular Germ Cell Tumor: UPenn Local TGCT Study

  Testicular germ cell tumors (TGCT) are the most common cancer in men ages 20-40. The incidence of TGCT has more than doubled over the past forty years, without clear etiology. Both genetic effects and environmental exposures, specifically during the pre-natal period, are likely to play an important role in determining TGCT susceptibility. TGCT is known to develop from primordial germ cells (PGCs). We hypothesize that variation in genes that impact upon the differentiation and maturation of PGCs will be important determinants of TGCT susceptibility and based on this hypothesis have selected three important pathways for study, i) male germ cell development, ii) androgen and estrogen biosynthesis and metabolism, and iii) IGF signaling. The proteins involved in early male germ cell development, normally only expressed in PGCs, are markers of and are overexpressed in TGCT. Markers of increased exposure to estrogen (or relatively decreased exposure to androgen) in utero and exogenous estrogen exposures, such as endocrine disruptors, have been associated with TGCT case status in multiple studies. IGF signaling is necessary for testis differentiation and maturation in mice and interacts synergistically with the estrogen signaling pathway. Additionally, we are interested in examining genetic factors predisposing to TGCT in an unbiased fashion, and thus will conduct a Genome Wide Association Study. As well disease susceptiblity, genetics are likely to play a role in disease progression, disease outcomes and response to treatement. We will also assess association of inherited genetics with these outcomes. We will analyze the contribution of genetic variants in these pathways to TGCT risk using a population-based case-control study in the Philadelphia metropolitian area. Our goal is the collection of 550 TGCT cases and 1100 age, race and cell phone use matched controls without a history of TGCT, which will yield 500 and 1000 white cases and controls, respectively, available for final analyses. All cases will be enumerated through the New Jersey and Pennsylvania state cancer registries. We will use a two-tiered approach for case recruitment: hospital clinic-based followed by registry-based. Hospital based cases will be identified within the Univeristy of Pennsylvania Health System and the University of Pennsylvania Cancer Network. All cases identified through this mechanism will be recruited irregardless of diagnosis date. The remaining cases will be identified through the New Jersey and Pennsylvania cancer registries and contacted following their protocols. Controls will be identified through random digit dialing and address based sampling. Both cases and controls will complete a questionnaire addressing known, presumed, and hypothesized risk factors for TGCT and provide a biospecimen. Pathological slides will be reviewed to cases to confirm diagnostic sub-type of TGCT. Haplotypes and functional SNPs will be typed in the genes of interest, as well as throughout the genome. Analyses will be conducted for specific variants, common haplotypes, alone and in conjunction with each other and exposure data after appropriate adjustment for potential confounders. The findings from this study will greatly contribute to our understanding of determinants of TGCT susceptibility.

  Study phs001307

• Analysis of CD20 loss in patients treated with Mosunetuzumab

  CD20 is an established therapeutic target in B-cell malignancies. The CD20xCD3 bispecific antibody mosunetuzumab has significant efficacy in B-cell non-Hodgkin lymphomas (NHL). Since target antigen loss is a recognized mechanism of resistance, we evaluated the contribution of CD20 expression to clinical response in patients with relapsed and/or refractory NHL in the phase 1/2 GO29781 trial (ClinicalTrials.gov: NCT02500407) investigating mosunetuzumab monotherapy. CD20 was studied using immunohistochemistry (IHC), RNA sequencing, and whole-exome sequencing performed centrally in biopsies collected prior to treatment, or as paired samples at pre-dose and on-treatment, or at-progression. Prior to treatment, most patients exhibited a high proportion of tumor cells expressing CD20; however, the proportion of CD20+ tumor cells in 14/293 (6%) patients was <10%. Analyses of paired biopsies from patients during treatment revealed that CD20 levels were maintained in 29/30 (97%), vs patients with samples at-progression, in which 11/32 (34%) showed CD20 loss. Reduced transcription or acquisition of truncating mutations explained most but not all cases of CD20 loss. In vitro modeling confirmed the effect of CD20 variants identified in clinical samples on reduction of CD20 expression and confirmed missense mutations in the extracellular domain that could block mosunetuzumab binding. This study expands knowledge about the occurrence of target antigen loss after anti-CD20 therapeutics to CD20-targeting bispecific antibodies and elucidates the underlying mechanisms for reduced CD20 expression at disease progression that may be generalizable to other anti-CD20 targeting agents. These results also establish the utility of readily-available IHC staining for CD20 as a tool to inform clinical decisions.

  Study EGAS50000000151

• International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN)

  The genetic makeup of an individual strongly influences the risk of developing systemic lupus erythematosus (SLE). The identification of genes that predispose an individual to SLE will lead to earlier and better diagnosis, better treatments, and possibly prevention. To this end, the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) was formed in 2005 and is composed of lupus researchers who agreed to pool their knowledge and resources to search for genes that predispose to lupus. Eight laboratories contributed DNA samples for genotyping at the Broad Institute and association with SLE was performed by the Data Coordinating Center (Wake Forest University), as part of a four stage study design. Stages one and two of this design were graciously funded by the Alliance for Lupus Research (www.lupusresearch.org). In this stage of the study, approximately 767 SLE patients (cases) were compared to approximately 383 non-SLE patients (controls) for differences among the Illumina HumanHap300. The affected individuals are all females of European decent. 82% of the cases are the index case from multiplex pedigrees for SLE and the remaining 18% have self-reported first degree relatives with SLE. A detailed summary of the methods and results can be found in the manuscript in Nature Genetics February 2008 by SLEGEN "Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants ITGAM, PXK, KIAA1542 and other loci". (Please see also Study Accession: phs000202.v1.p1)

  Study phs000216