Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family.

Background: Germline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants.

Methods: The proband was tested via a clinical testing, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT).

Expanded genetic testing of GIST patients identifies high proportion of non-syndromic patients with germline alterations.

Traditional genetic testing for patients with gastrointestinal stromal tumors (GISTs) focus on those with syndromic features. To assess whether expanded genetic testing of GIST patients could identify hereditary cancer predisposition, we analyzed matched tumor-germline sequencing results from 103 patients with GISTs over a 6-year period. Germline pathogenic/likely pathogenic (P/LP) variants in GIST-associated genes (SDHA, SDHB, SDHC, NF1, KIT) were identified in 69% of patients with KIT/PDGFRA-wildtype GISTs, 63% of whom did not have any personal or family history of syndromic features.

Methylation Analyses Reveal Promoter Hypermethylation as a Rare Cause of "Second Hit" in Germline BRCA1-Associated Pancreatic Ductal Adenocarcinoma.

Background And Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterized by the occurrence of pathogenic variants in BRCA1/2 in 5-6% of patients. Biallelic loss of BRCA1/2 enriches for response to platinum agents and poly (ADP-ribose) polymerase 1 inhibitors. There is a dearth of evidence on the mechanism of inactivation of the wild-type BRCA1 allele in PDAC tumors with a germline BRCA1 (gBRCA1) pathogenic or likely pathogenic variant (P/LPV).

Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients.

Background: Genetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary cancer gene panels uncovered hereditary predisposition in a greater proportion of patients than previously anticipated. We sought to define the diagnostic yield of eGT and its clinical relevance in a broad cancer patient population over a 5-year period.

Interest and Utility of Testing for Melanoma Risk in Dermatology Patients with a History of Nonmelanoma Skin Cancer.

Public access to genetic information is increasing, and community dermatologists may progressively encounter patients interested in genetic testing for melanoma risk. Clarifying potential utility will help plan for this inevitability. We determined interest and uptake of genetic risk feedback based on melanocortin receptor gene () variants, immediate (two weeks) responses to risk feedback, and test utility at three months in patients (age ≥ 18, with a history of nonmelanoma skin cancer).

Somatic intronic TP53 c.375+5G mutations are a recurrent but under-recognized mode of TP53 inactivation.

TP53 is one of the most ubiquitously altered genes in human cancer. The biological impact of rare variants, particularly those located within noncoding regions, remains poorly understood. From interrogation of clinical massively parallel sequencing data from over 55,000 tumors, which included 23,330 tumors with known TP53 mutations, TP53 intron 4 nucleotide substitutions at position c.

Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072).

Paired Tumor-Normal Sequencing Provides Insights Into the TP53-Related Cancer Spectrum in Patients With Li-Fraumeni Syndrome.

Background: Genetic testing for Li-Fraumeni syndrome (LFS) is performed by using blood specimens from patients selected based on phenotype-dependent guidelines. This approach is problematic for understanding the LFS clinical spectrum because patients with nonclassical presentations are missed, clonal hematopoiesis-related somatic blood alterations cannot be distinguished from germline variants, and unrelated tumors cannot be differentiated from those driven by germline TP53 defects.

Methods: To provide insights into the LFS-related cancer spectrum, we analyzed paired tumor-blood DNA sequencing results in 17 922 patients with cancer and distinguished clonal hematopoiesis-related, mosaic, and germline TP53 variants.

Insertion of an SVA element in MSH2 as a novel cause of Lynch syndrome.

Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome (LS). In this study, we identified and characterized a novel SINE-VNTR-Alu (SVA) insertion in exon 12 of MSH2 in an individual with early-onset colorectal cancer and a very strong LS family history. RT-PCR analysis indicated a larger aberrant MSH2 transcript in one of the family members.

The RAD51D c.82G>A (p.Val28Met) variant disrupts normal splicing and is associated with hereditary ovarian cancer.

Purpose: Mutations in RAD51D are associated with a predisposition to primary ovarian, fallopian tube, and peritoneal carcinoma. Our study aims to characterize a RAD51D missense variant in a hereditary ovarian cancer family.

Methods: The effects of the RAD51D c.

The Proteasome Activators Blm10/PA200 Enhance the Proteasomal Degradation of N-Terminal Huntingtin.

The Blm10/PA200 family of proteasome activators modulates the peptidase activity of the core particle (20S CP). They participate in opening the 20S CP gate, thus facilitating the degradation of unstructured proteins such as tau and Dnm1 in a ubiquitin- and ATP-independent manner. Furthermore, PA200 also participates in the degradation of acetylated histones.

Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family.

Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome. Classification and interpretation of intronic variants, especially those outside the consensus ± 1 ~ 2 splice sites are challenging as it is uncertain whether such variants would affect splicing accuracy and efficiency. The assessment of the pathogenicity of splice site variants in MLH1 is further complicated by the various isoforms due to alternative splicing.

Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma.

Fumarate hydratase (FH) mutations underpin the autosomal recessive syndrome. FH deficiency and the autosomal dominant syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH c.

A synonymous germline variant PALB2 c.18G>T (p.Gly6=) disrupts normal splicing in a family with pancreatic and breast cancers.

Purpose: Mutations in PALB2 have been associated with a predisposition to breast and pancreatic cancers. This study aims to characterize a novel PALB2 synonymous variant c.18G>T (p.

Germline mutations in children and adults with cancer.

Mutations in succinate dehydrogenase complex genes predispose to familial paraganglioma-pheochromocytoma syndrome (FPG) and gastrointestinal stromal tumors (GIST). Here we describe cancer patients undergoing agnostic germline testing at Memorial Sloan Kettering Cancer Center and found to harbor germline mutations. Using targeted sequencing covering the cancer census genes, we identified 10 patients with germline mutations.

Characterization of a novel germline BRCA1 splice variant, c.5332+4delA.

Purpose: Germline mutations in BRCA1 and BRCA2 confer a significant increase in risk for cancer, and determining pathogenicity of a BRCA variant can guide the clinical management of the disease. About 1/3 of BRCA1 variants reported in the public databases have uncertain clinical significance due to lack of conclusive evidence. This study aims to characterize a novel BRCA1 deletion affecting the + 4 splice donor site identified in an individual with early-onset breast cancer.

Characterization of a novel germline PALB2 duplication in a hereditary breast and ovarian cancer family.

Purpose: Mutations in PALB2 have been associated with a predisposition to breast and pancreatic cancers. This study aims to characterize a novel PALB2 exon 13 duplication in a hereditary breast and ovarian cancer family.

Methods: The PALB2 exon 13 duplication in this family was evaluated using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT™) and confirmed by multiplex ligation-dependent probe amplification (MLPA).

Analysis of the Yeast Peptidome and Comparison with the Human Peptidome.

Peptides function as signaling molecules in species as diverse as humans and yeast. Mass spectrometry-based peptidomics techniques provide a relatively unbiased method to assess the peptidome of biological samples. In the present study, we used a quantitative peptidomic technique to characterize the peptidome of the yeast Saccharomyces cerevisiae and compare it to the peptidomes of mammalian cell lines and tissues.

Proteasomes, Sir2, and Hxk2 form an interconnected aging network that impinges on the AMPK/Snf1-regulated transcriptional repressor Mig1.

Elevated proteasome activity extends lifespan in model organisms such as yeast, worms and flies. This pro-longevity effect might be mediated by improved protein homeostasis, as this protease is an integral module of the protein homeostasis network. Proteasomes also regulate cellular processes through temporal and spatial degradation of signaling pathway components.

Proteasome inhibitors alter levels of intracellular peptides in HEK293T and SH-SY5Y cells.

The proteasome cleaves intracellular proteins into peptides. Earlier studies found that treatment of human embryonic kidney 293T (HEK293T) cells with epoxomicin (an irreversible proteasome inhibitor) generally caused a decrease in levels of intracellular peptides. However, bortezomib (an antitumor drug and proteasome inhibitor) caused an unexpected increase in the levels of most intracellular peptides in HEK293T and SH-SY5Y cells.

Cutting through complexity: the proteolytic properties of alternate immunoproteasome complexes.

The proteasome core interacts with different activators and incorporates alternate active subunits, thereby generating a diverse pool of subspecies. The enzymatic properties of these different species are not well understood. In this issue of Chemistry & Biology, Raule and colleagues present a comprehensive enzymatic characterization of immunoproteasome complexes associated with the proteasome activator PA28.

Proteasomes associated with the Blm10 activator protein antagonize mitochondrial fission through degradation of the fission protein Dnm1.

The conserved Blm10/PA200 activators bind to the proteasome core particle gate and facilitate turnover of peptides and unfolded proteins in vitro. We report here that Blm10 is required for the maintenance of functional mitochondria. BLM10 expression is induced 25-fold upon a switch from fermentation to oxidative metabolism.

WITHDRAWN: Blm10-proteasomes antagonize mitochondrial fission through degradation of Dnm1.

This manuscript was withdrawn by the author.