cancer predisposition syndrome
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Author(s):  
Amanda de Andrade Costa ◽  
Jit Chatterjee ◽  
Olivia Cobb ◽  
Elizabeth Cordell ◽  
Astoria Chao ◽  
...  

Abstract Background Brain tumor formation and progression are dictated by cooperative interactions between neoplastic and non-neoplastic cells. This stromal dependence is nicely illustrated by tumors arising in the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome, where children develop low-grade optic pathway gliomas (OPGs). Using several authenticated Nf1-OPG murine models, we previously demonstrated that murine Nf1-OPG growth is regulated by T cell function and microglia Ccl5 production, such that their inhibition reduces tumor proliferation in vivo. While these interactions are critical for established Nf1-OPG tumor growth, their importance in tumor formation has not been explored. Methods A combination of bulk and single cell RNA mouse optic nerve sequencing, immunohistochemistry, T cell assays, and pharmacologic and antibody-mediated inhibition methods were used in these experiments. Results We show that T cells and microglia are the main non-neoplastic immune cell populations in both murine and human LGGs. Moreover, we demonstrate that CD8 + T cells, the predominant LGG-infiltrating lymphocyte population, are selectively recruited through increased Ccl2 receptor (Ccr4) expression in CD8 +, but not CD4 +, T cells, in a NF1/RAS-dependent manner. Finally, we identify the times during gliomagenesis when microglia Ccl5 production (3-6 weeks of age) and Ccl2-mediated T cell infiltration (7-10 weeks of age) occur, such that temporally-restricted Ccl2 or Ccl5 inhibition abrogates tumor formation >3.5 months following the cessation of treatment. Conclusions Collectively, these findings provide proof-of-concept demonstrations that targeting stromal support during early gliomagenesis durably blocks murine LGG formation.


Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 56
Author(s):  
Jeffrey M. Lipton ◽  
Christine L. S. Molmenti ◽  
Pooja Desai ◽  
Alexander Lipton ◽  
Steven R. Ellis ◽  
...  

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome, the founding member of a class of disorders known as ribosomopathies. Most cases result from loss of function mutations or deletions in 1 of 23 genes encoding either a small or large subunit-associated ribosomal protein (RP), resulting in RP haploinsufficiency. DBA is characterized by red cell hypoplasia or aplasia, poor linear growth and congenital anomalies. Small case series and case reports demonstrate DBA to be a cancer predisposition syndrome. Recent analyses from the Diamond Blackfan Anemia Registry of North America (DBAR) have quantified the cancer risk in DBA. These studies reveal the most prevalent solid tumor, presenting in young adults and in children and adolescents, to be colorectal cancer (CRC) and osteogenic sarcoma, respectively. Of concern is that these cancers are typically detected at an advanced stage in patients who, because of their constitutional bone marrow failure, may not tolerate full-dose chemotherapy. Thus, the inability to provide optimal therapy contributes to poor outcomes. CRC screening in individuals over the age of 50 years, and now 45 years, has led to early detection and significant improvements in outcomes for non-DBA patients with CRC. These screening and surveillance strategies have been adapted to detect familial early onset CRC. With the recognition of DBA as a moderately penetrant cancer risk syndrome a rational screening and surveillance strategy will be implemented. The downstream molecular events, resulting from RP haploinsufficiency and leading to cancer, are the subject of significant scientific inquiry.


Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 10
Author(s):  
Yan Zhou ◽  
Andrew C. Nelson ◽  
Yuyu He ◽  
Sarah A. Munro ◽  
Kyu Young Song ◽  
...  

BAP-1 (BRCA1-associated protein 1) inactivated melanocytic lesions are a group of familial or sporadic lesions with unique histology and molecular features. They are of great clinical interest, at least in part due to the potential for malignant transformation and association with a familial cancer predisposition syndrome. Here, we describe a patient with multiple spatially and temporally distinct melanocytic lesions with loss of BAP1 expression by immunohistochemistry. RNA sequencing was performed on three independent lesions spanning the morphologic spectrum: a benign nevus, an atypical tumor, and a melanoma arising from a pre-existing BAP1-inactivated nevus. The three lesions demonstrated largely distinct gene expression and mutational profiles. Gene expression analysis revealed that genes involved in receptor protein kinase pathways were progressively upregulated from nevus to melanoma. Moreover, a clear enrichment of genes regulated in response to UV radiation was found in the melanoma from this patient, as well as upregulation of MAPK pathway-related genes and several transcription factors related to melanomagenesis.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3400
Author(s):  
Megan R. Reed ◽  
A. Geoffrey Lyle ◽  
Annick De Loose ◽  
Leena Maddukuri ◽  
Katrina Learned ◽  
...  

Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30–50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.


Blood ◽  
2021 ◽  
Author(s):  
Margaret A Ferris ◽  
Amanda M Smith ◽  
Sharon E Heath ◽  
Eric J Duncavage ◽  
Matthew J Oberley ◽  
...  

DNMT3A Overgrowth Syndrome (DOS, also known as Tatton-Brown Rahman Syndrome/TBRS) is one of several overgrowth syndromes with complex phenotypes caused by constitutional mutations in genes encoding epigenetic regulators. The clinical features of DOS are variable but include overgrowth (tall stature and/or obesity) and intellectual disability. DNMT3A is essential for de novo DNA methylation and plays an important role in hematopoiesis. Somatic mutations in DNMT3A are among the most common initiating mutations in normal karyotype acute myeloid leukemia (AML) patients and in elderly people with clonal hematopoiesis. The natural history of DOS has not been fully explored since the first description of this rare condition in 2014. Because of the association of somatic DNMT3A mutations and leukemia development, we assessed information from the ~200 known DOS patients world-wide and were able to document eight with hematologic malignancies. Based on this prevalence, we suggest DOS is a cancer predisposition syndrome, especially for hematologic malignancies. Using recommendations from an expert panel, we suggest DOS patients should be prospectively monitored for hematologic malignancies, which may allow for early intervention and permit its natural history to be better defined.


Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5743
Author(s):  
Nils Welter ◽  
Angelo Wagner ◽  
Rhoikos Furtwängler ◽  
Patrick Melchior ◽  
Leo Kager ◽  
...  

Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith–Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys–Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3385-3385
Author(s):  
Brittany L Griffin ◽  
Navneet S. Majhail ◽  
Harry Lesmana

Abstract MBD4, a gene encoding a DNA glycosylase functioning in base excision repair, has recently been described in association with predisposition to early onset acute myeloid leukemia (AML), uveal melanoma and colorectal polyposis. MBD4 is essential for guarding against methylation damage due to spontaneous deamination of 5-methylcytosine and biallelic loss of MBD4 allows CG>TG mutations to accumulate in the genome predisposing to AML (Sanders et al. Blood 2018). Further understanding of the full phenotypic spectrum and mechanisms leading to cancer evolution for this predisposition syndrome is critical for informing early recognition, diagnosis, management, and treatment for these individuals and their at-risk family members with the ultimate goal of improving outcomes. Here we report novel germline mutations in MBD4, expand the spectrum of cancers and describe the mutational signatures associated with this cancer predisposition syndrome. Two siblings (brother and sister) from a non-consanguineous family with strong family history of cancers were diagnosed with early-onset AML and colorectal polyposis in their 30s. Prior to the diagnosis of AML, the brother was diagnosed with colorectal cancer and lymphoma at 24 and 28 years old respectively. He was diagnosed with AML at 30 years old and underwent allogenic hematopoietic stem cell transplant (HSCT) using her sister as donor but subsequently passed away following relapse of his AML. The sister was diagnosed with colorectal polyposis at 33 years old and underwent total colectomy due to numerous (>70) hyperplastic and adenomatous colorectal polyps. At the age of 35 years old she was diagnosed with AML after presenting with progressive peripheral cytopenias, lymphadenopathy and splenomegaly. Her AML was characterized by normal karyotype and absent of NPM1, CEBPA and FLT3 aberrations. Further molecular profiling using targeted myeloid NGS panel identified multiple C>T missense mutations including hotspot DNMT3A mutation c.2644C>T, p.R882C (Table 1). SNP microarray revealed balanced genome but identified copy loss of heterozygosity in chromosome 1p and 1q. She received two cycles of remission induction chemotherapy (7+3 regimen) and achieved remission prior to allogenic HSCT using matched unrelated donor. Her post-transplant course was complicated by chronic graft versus host disease treated with tacrolimus. She currently remains in remission now six years post-transplant. She later developed papillary thyroid carcinoma at the age of 44 for which she underwent total thyroidectomy. Shortly after, she was evaluated with brain MRI due to sensorineural hearing loss, which identified bilateral vestibular schwannoma. Her right schwannoma was resected and the smaller, left schwannoma is being monitored. Tumor profiling on tissue from the right schwannoma detected two C>T truncating mutations in NF2 as well as multiple other C>T missense variants resulting in high tumor mutational burden calculated at 16.8 mutations/MB (Table 1). Tumor profiling performed on tissue from her thyroid carcinoma is pending. Due to concern for germline cancer predisposition syndrome, whole exome sequencing was performed and identified two germline nonsense variants in MBD4 c.1291 C>T, p.Arg431* and c.1688 T>A, p.Leu563* in trans configuration. These truncating variants are located in the glycosylase domain of MBD4 and predicted to abolish the catalytic function of the gene (Figure 1). Both truncating variants (Arg431* and Leu563*) are present in gnomAD with very low allele frequency of 3.18 X 10 -5 and 7.04 X 10 -5 respectively. No additional germline mutations were identified. This case further validates the role of MBD4 as germline predisposition to myeloid malignancies characterized by hyper-mutated genomic signatures. Additionally we expanded the spectrum of cancers associated with this novel cancer predisposition syndrome to include papillary thyroid carcinoma and vestibular schwannomas. Genomic profiling of the normal and affected tissue identified germline bi-allelic loss of function mutation in MBD4 as initiator of methylation defect in key driver genes in tissue specific manner leading to carcinogenesis. This conserved path to mutagenesis is unique to this cancer predisposition syndrome and further biological studies are needed to fully understand the spectrum of cancers associated with this syndrome. Figure 1 Figure 1. Disclosures Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi212-vi212
Author(s):  
Yuan Pan ◽  
Jared Hysinger ◽  
Tara Barron ◽  
Nicki Schindler ◽  
Olivia Cobb ◽  
...  

Abstract Neurons have recently emerged as essential cellular constituents of the tumor microenvironment, where their activity increases the growth of a diverse number of solid tumors. While the role of neurons in tumor progression has been previously demonstrated, the importance of neuronal activity to tumor initiation is less clear, particularly in the setting of cancer predisposition syndromes. In the Neurofibromatosis-1 (NF1) cancer predisposition syndrome, in which tumors arise in close association with nerves, 15% of individuals develop low-grade neoplasms of the optic pathway (optic pathway gliomas [OPGs]), during early childhood, raising the intriguing possibility that postnatal light-induced optic nerve activity drives tumor initiation. Here, we employ an authenticated murine model of Nf1-OPG to demonstrate that stimulation of optic nerve activity increases optic glioma growth, while decreasing visual experience via light deprivation prevents tumor formation and maintenance. We show that Nf1-OPG initiation depends on visual experience during a developmental period susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly high optic nerve neuroligin-3 (Nlgn3) shedding in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of Nlgn3 shedding blocks murine Nf1 optic gliomagenesis and progression. Collectively, these studies establish an obligate role for neuronal activity in the development of certain brain tumors, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumor progression, and underscore the role of Nf1 mutation-mediated dysregulation of neuronal signaling pathways in the NF1 cancer predisposition syndrome.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Nicolas Waespe ◽  
Sven Strebel ◽  
Denis Marino ◽  
Veneranda Mattiello ◽  
Fanny Muet ◽  
...  

Abstract Background Research on germline genetic variants relies on enough eligible participants which is difficult to achieve for rare diseases such as childhood cancer. With self-collection kits, participants can contribute genetic samples conveniently from their home. Demographic and clinical factors were identified previously that influenced participation in mailed self-collection. People with pre-existing heritable diagnoses might participate differently in germline DNA collection which might render sampling biased in this group. In this nationwide cross-sectional study, we analysed predictive factors of participation in DNA self-collection including heritable diagnoses. Methods We identified childhood cancer survivors from the Swiss Childhood Cancer Registry for invitation to germline DNA self-sampling in September 2019. Participants received saliva sampling kits by postal mail at their home, were asked to fill them, sign an informed consent, and send them back by mail. Two reminders were sent to non-participants by mail. We compared demographic, clinical, and treatment information of participants with non-participants using univariable and multivariable logistic regression models. Results We invited 928 childhood cancer survivors in Switzerland with a median age of 26.5 years (interquartile range 19-37), of which 463 (50%) participated. After the initial send out of the sampling kit, 291 (63%) had participated, while reminder letters led to 172 additional participants (37%). Foreign nationality (odds ratio [OR] 0.5; 95%-confidence interval [CI] 0.4-0.7), survivors aged 30-39 years at study versus other age groups (OR 0.5; CI 0.4-0.8), and survivors with a known cancer predisposition syndrome (OR 0.5; CI 0.3-1.0) were less likely to participate in germline DNA collection. Survivors with a second primary neoplasm (OR 1.9; CI 1.0-3.8) or those living in a French or Italian speaking region (OR 1.3; CI 1.0-1.8) tended to participate more. Conclusions We showed that half of childhood cancer survivors participated in germline DNA self-sampling relying completely on mailing of sample kits. Written reminders increased the response by about one third. More targeted recruitment strategies may be advocated for people of foreign nationality, aged 30-39 years, and those with cancer predisposition syndromes. Perceptions of genetic research and potential barriers to participation of survivors need to be better understood. Trial registration Biobank: https://directory.bbmri-eric.eu/#/collection/bbmri-eric:ID:CH_HopitauxUniversitairesGeneve:collection:CH_BaHOP Research project: Clinicaltrials.gov: NCT04702321.


Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1736
Author(s):  
Ahmed Bouras ◽  
Melanie Leone ◽  
Valerie Bonadona ◽  
Marine Lebrun ◽  
Alain Calender ◽  
...  

Hereditary breast and ovarian cancer syndrome (HBOC) is an autosomal dominant cancer predisposition syndrome characterized by an increased risk of breast and ovarian cancers. Germline pathogenic variants in BRCA1 are found in about 7–10% of all familial breast cancers and 10% of ovarian cancers. Alu elements are the most abundant mobile DNA element in the human genome and are known to affect the human genome by different mechanisms leading to human disease. We report here the detection, by next-generation sequencing (NGS) analysis coupled with a suitable bioinformatics pipeline, of an AluYb8 element in exon 14 of the BRCA1 gene in a family with HBOC history first classified as BRCA-negative by Sanger sequencing and first NGS analysis. The c.4475_c.4476insAluYb8 mutation impacts splicing and induces the skipping of exon 14. As a result, the produced mRNA contains a premature stop, leading to the production of a short and likely non-functional protein (pAla1453Glyfs*10). Overall, our study allowed us to identify a novel pathogenic variant in BRCA1 and showed the importance of bioinformatics tool improvement and versioning.


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