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• MutWP5__CRUK_Mutographs_of_Cancer__BRCA_Carriers___Exome__Novaseq_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003526

• The chromatin accessibility signature of human immune aging stems from CD8+ T cells

  Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel the regulatory programsbehind these changes, we applied systems immunology approaches and profiled chromatin accessibility and the transcriptomein PBMCs, purified monocytes, and B and T cells. Analysis of samples from 77 young and elderly donors revealed a novel androbust aging signature in PBMCs, with simultaneous systematic chromatin closing at promoters and enhancers associated withT cell signaling and a potentially stochastic chromatin opening mostly found at quiescent and repressed sites. Combined analysesof chromatin accessibility and the transcriptome uncovered immune molecules activated/inactivated with aging andidentified the silencing of the IL7R gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borneby memory CD8+ T cells, which exhibited an aging-related loss in binding of NF-κB and STAT factors. Thus, our study providesa unique and comprehensive approach to identifying candidate biomarkers and provides mechanistic insights into aging-associatedimmunodeficiency.

  Study EGAS00001002605

• Neuroblastoma heterogeneity

  Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although certain complex genomic alterations, such as extrachromosomal DNA amplifications (ecDNA), are associated with adverse outcomes and have been recurrently detected in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography of complex rearrangements along with mutational signatures derived from all variant classes, we identify previously unrecognized co-occurring mutational footprints, which we termed mutational scenarios. We demonstrate that clinical neuroblastoma heterogeneity is linked to differences in the processes driving these mutational scenarios. Whereas high-risk MYCN-amplified neuroblastoma genomes were characterized by signs of replication slippage and stress, homologous recombination-associated signatures defined high-risk non-MYCN-amplified patients. Non-high-risk neuroblastomas, on the other hand, were marked by footprints of chromosome missegregation and TOP1 mutational activity. This analysis provides a systematic perspective on the repertoire of mutational patterns that contribute to clinical neuroblastoma heterogeneity.

  Study EGAS00001007016

• Transcriptional mechanisms of resistance to anti-PD-1 therapy

  Purpose: To explore factors associated with response and resistance to anti-PD-1 therapy, we analyzed multiple disease sites at autopsy in a patient with widely metastatic melanoma who had a heterogeneous response.Materials and Methods: Twenty-six melanoma specimens (four pre-mortem, 22 post-mortem) were subjected to whole-exome sequencing. Candidate immunologic markers and gene expression were assessed in ten cutaneous metastases showing response or progression during therapy.Results: The melanoma was driven by biallelic inactivation of NF1. All lesions had highly concordant mutational profiles and copy number alterations, indicating linear clonal evolution. Expression of candidate immunologic markers was similar in responding and progressing lesions. However, progressing cutaneous metastases were associated with over-expression of genes associated with extracellular matrix and neutrophil function.Conclusions: Although mutational and immunologic differences have been proposed as the primary determinants of heterogeneous response/resistance to targeted therapies and immunotherapies, respectively, differential lesional gene expression profiles may also dictate anti-PD-1 outcomes.

  Study EGAS00001002195

• Somatic_mutation_and_clonal_evolution_normal_breast_tissue_TGS

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >70 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumour development.

  Study EGAS00001002858

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Reduction_Mammoplasty__WG_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003311

• MutWP5__CRUK_Mutographs_of_Cancer__BRCA_Carriers___WG__Novaseq_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003523

• Whole-exome sequencing reveals the origin and evolution of Hepato-Cholangiocarcinoma

  Hepatocellular-cholangiocarcinoma (H-ChC) is a rare subtype of liver cancer with clinicopathological features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). To date, molecular mechanisms underlying the co-existence of HCC and iCCA components in a single tumor remain elusive. Here we show that H-ChC samples contain substantial private mutations from WES analyses, ranging from 33.1% to 86.4%, indicative of substantive intratumor heterogeneity (ITH). However, on the other hand, numerous ubiquitous mutations shared by HCC and iCCA suggest the monoclonal origin of H-ChC. Mutated genes identify herein e.g. VCAN, ACVR2A and FCGBP are speculated to contribute to distinct differentiation of HCC and iCCA within H-ChC. Moreover, immunohistochemistry demonstrate that EpCAM is highly expressed in 80% of H-ChC implying the stemness of such liver cancer. In summary, our data highlight the monoclonal origin and stemness of H-ChC, as well as substantial intratumoral heterogeneity.

  Study EGAS00001002783

• Exome and RNA sequencing data from 32 ocular and extraocular sebaceous carcinomas

  Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominated 10/32 samples, while 9 were instead defined by microsatellite instability (MSI) mutations. UV-damage SeC exhibited poorly differentiated, infiltrative histopathologycompared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Strikingly, UV-damage SeC transcriptomes and anatomic distributionclosely resembling those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations/Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquire far fewer mutations without a dominant signature, but show frequent truncating mutations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers.

  Study EGAS00001002869

• MutWP5__CRUK_Mutographs_of_Cancer__Breast__Reduction_Mammoplasty__Exome_

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >60 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumor development.

  Study EGAS00001003313