Showing papers by "Mark Pinese published in 2019"

CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

Abstract: Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.

Therapeutic implications of germline genetic findings in cancer

Abstract: Cancer is a genetic disease. To date, translational cancer genomics has focused largely on somatic alterations, driven by the desire to identify targets for personalized therapy. However, therapeutically relevant information is also latent within the germline genome. In addition to cancer susceptibility, alterations present in the germ line can determine responses to both targeted and more traditional anticancer therapies, as well as their toxicities. Despite the importance of these alterations, many algorithms designed to analyse somatic mutations conversely continue to subtract information on germline genetics during analysis. In the light of low actionable yields from somatic tumour testing, a need exists for diversification of the sources of potential therapeutic biomarkers. In this Review, we summarize the literature on the therapeutic potential of alterations in the germline genome. The therapeutic value of germline information will not only be manifest as improvements in treatment but will also drive greater levels of engagement and cooperation between traditional oncology services and familial risk management clinics. The majority of genetically targeted approaches to cancer therapy focus on somatic mutations. However, evidence is accumulating in support of a role for germline genetic alterations in determining responsiveness to treatment. In this Review, the authors summarize the therapeutic potential of knowledge of the germline genome in patients with cancer.

The Medical Genome Reference Bank: a whole-genome data resource of 4000 healthy elderly individuals. Rationale and cohort design

Abstract: Allele frequency data from human reference populations is of increasing value for the filtering, interpretation, and assignment of pathogenicity to genetic variants. Aged and healthy populations are more likely to be selectively depleted of pathogenic alleles and therefore particularly suitable as a reference population for the major diseases of clinical and public health importance. However, reference studies of confirmed healthy elderly individuals have remained under-represented in human genetics. Here we describe the Medical Genome Reference Bank (MGRB), a large-scale comprehensive whole-genome data set of healthy elderly individuals. The MGRB provides an accessible data resource for health-related research and clinical genetics and a powerful platform for studying the genetics of healthy ageing. The MGRB is comprised of 4000 healthy, older individuals, mostly of European descent, recruited from two Australian community-based cohorts. Each participant lived ≥70 years with no reported history of cancer, cardiovascular disease, or dementia. DNA derived from blood samples has been subject to whole-genome sequencing. The MGRB has committed to a policy of data sharing, employing a hierarchical data management system to maintain participant privacy and confidentiality, while maximising research and clinical usage of the database. The MGRB represents a resource of international significance, which will be made broadly accessible to the clinical and genetic research community.

mity: A highly sensitive mitochondrial variant analysis pipeline for whole genome sequencing data

Abstract: Motivation Mitochondrial diseases (MDs) are the most common group of inherited metabolic disorders and are often challenging to diagnose due to extensive genotype-phenotype heterogeneity. MDs are caused by mutations in the nuclear or mitochondrial genome, where pathogenic mitochondrial variants are usually heteroplasmic and typically at much lower allelic fraction in the blood than affected tissues. Both genomes can now be readily analysed using unbiased whole genome sequencing (WGS), but most nuclear variant detection methods fail to detect low heteroplasmy variants in the mitochondrial genome. Results We present mity, a bioinformatics pipeline for detecting and interpreting heteroplasmic SNVs and INDELs in the mitochondrial genome using WGS data. In 2,980 healthy controls, we observed on average 3,166× coverage in the mitochondrial genome using WGS from blood. mity utilises this high depth to detect pathogenic mitochondrial variants, even at low heteroplasmy. mity enables easy interpretation of mitochondrial variants and can be incorporated into existing diagnostic WGS pipelines. This could simplify the diagnostic pathway, avoid invasive tissue biopsies and increase the diagnostic rate for MDs and other conditions caused by impaired mitochondrial function. Availability mity is available from https://github.com/KCCG/mityunder an MIT license. Contact clare.puttick@crick.ac.uk, carolyn.sue@sydney.edu.au, MCowley@ccia.org.au

Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases

Abstract: Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 years using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2, TP53, RB1, and PTEN, resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression; however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.

Translating genomic risk into an early detection strategy for sarcoma.

Abstract: Sarcomas have a strong genetic etiology, and the study of families affected by sarcomas has informed much of what we now understand of modern cancer biology. The recent emergence of powerful genetic technologies has led to astonishing reductions in costs and increased throughput. In the clinic, these technologies are revealing a previously unappreciated and rich landscape of genetic cancer risk. In addition to both known and new cancer risk mutations, genomic tools are cataloguing complex and polygenic risk patterns, collectively explaining between 15-25% of apparently sporadic sarcoma cases. The impact on clinical management is exemplified by Li-Fraumeni Syndrome, the most penetrant sarcoma syndrome. Whole body magnetic resonance imaging can identify surgically resectable cancers in up to one in ten individuals with Li-Fraumeni Syndrome. Taken together, parallel developments in genomics, therapeutics and imaging technologies will drive closer engagement between genetics and multidisciplinary care of the sarcoma patient in the 21st century.

Identification of novel sarcoma risk genes using a two-stage genome wide DNA sequencing strategy in cancer cluster families and population case and control cohorts

Abstract: Although familial clustering of cancers is relatively common, only a small proportion of familial cancer risk can be explained by known cancer predisposition genes. In this study we employed a two-stage approach to identify candidate sarcoma risk genes. First, we conducted whole exome sequencing in three multigenerational cancer families ascertained through a sarcoma proband (n = 19) in order to prioritize candidate genes for validation in an independent case-control cohort of sarcoma patients using family-based association and segregation analysis. The second stage employed a burden analysis of rare variants within prioritized candidate genes identified from stage one in 560 sarcoma cases and 1144 healthy ageing controls, for which whole genome sequence was available. Variants from eight genes were identified in stage one. Following gene-based burden testing and after correction for multiple testing, two of these genes, ABCB5 and C16orf96, were determined to show statistically significant association with cancer. The ABCB5 gene was found to have a higher burden of putative regulatory variants (OR = 4.9, p-value = 0.007, q-value = 0.04) based on allele counts in sarcoma cases compared to controls. C16orf96, was found to have a significantly lower burden (OR = 0.58, p-value = 0.0004, q-value = 0.003) of regulatory variants in controls compared to sarcoma cases. Based on these genetic association data we propose that ABCB5 and C16orf96 are novel candidate risk genes for sarcoma. Although neither of these two genes have been previously associated with sarcoma, ABCB5 has been shown to share clinical drug resistance associations with melanoma and leukaemia and C16orf96 shares regulatory elements with genes that are involved with TNF-alpha mediated apoptosis in a p53/TP53-dependent manner. Future genetic studies in other family and population cohorts will be required for further validation of these novel findings.

The Cancer Molecular Screening and Therapeutics Program (MoST): Actionable mutation frequencies in a population with rare and less common cancers.

Abstract: 3136Background: Personalizing therapy will arguably have no greater impact than on patients (pts) with rare (< 6 per 100,000 population) or less common cancers (6-12/100,000). MoST combines a molec...

Author Correction: Therapeutic implications of germline genetic findings in cancer.

Abstract: The originally published article contained errors in the main text and in figure 1 in the reported number of patients with pathogenic or likely pathogenic germline variants. The originally reported numbers did not take into account the presence of more than one variant in an individual patient. This has been corrected in the HTML and PDF versions of the manuscript.