MicroED Characterization of a Robust Cationic -Alkane Complex Stabilized by the [B(3,5-(SF5)2C6H3)4]– Anion, via On-Grid Solid/Gas Single-Crystal to Single-Crystal Reactivity

Microcrystalline (~1 m) [Rh(Cy2PCH2CH2PCy2)(norbornadiene)][S-BArF4], [S-BArF4] = [B(3,5-(SF5)2C6H3)4]–, reacts with H2 in a single-crystal to single-crystal transformation to form the -alkane complex [Rh(Cy2PCH2CH2PCy2)(norbornane)][S-BArF4], for which the structure was determined by microcrystal Electron Diffraction (microED), to 0.95 Å resolution, via an on-grid hydrogenation, and a complementary single-crystal X-ray diffraction study on larger, but challenging to isolate, crystals. Comparison with the [BArF4]– analogue [ArF = 3,5-(CF3)2C5H3)] shows that the [S-BArF4]– anion makes the -alkane complex robust towards decomposition both thermally and when suspended in pentane. Subsequent reactivity with dissolved ethene in a pentane slurry, forms [Rh(Cy2PCH2CH2PCy2)(ethene)2][S-BArF4], and the catalytic dimerisation/isomerisation of ethene to 2-butenes. The increased stability of [S-BArF4]– salts is identified as being due to increased non-covalent interactions in the lattice, resulting in a solid-state molecular organometallic material with desirable stability characteristics

Periscope Proteins are variable length regulators of bacterial cell surface interactions

Changes at the cell surface enable bacteria to survive in dynamic environments, such as diverse niches of the human host. Here, we reveal “Periscope Proteins” as a widespread mechanism of bacterial surface alteration mediated through protein length variation. Tandem arrays of highly similar folded domains can form an elongated rod-like structure; thus, variation in the number of domains determines how far an N-terminal host ligand binding domain projects from the cell surface. Supported by newly available long-read genome sequencing data, we propose that this class could contain over 50 distinct proteins, including those implicated in host colonization and biofilm formation by human pathogens. In large multidomain proteins, sequence divergence between adjacent domains appears to reduce interdomain misfolding. Periscope Proteins break this “rule,” suggesting that their length variability plays an important role in regulating bacterial interactions with host surfaces, other bacteria, and the immune system

No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in mlh1 and msh2: A prospective lynch syndrome database study

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.Fil: Dominguez Valentin, Mev. St Mark’s Hospital; Reino Unido. The Norwegian Radium Hospital; Noruega. European Hereditary Tumour Group; Reino UnidoFil: Plazzer, John Paul. St Mark’s Hospital; Reino Unido. The Royal Melbourne Hospital; AustraliaFil: Sampson, Julian R.. European Hereditary Tumour Group; Reino Unido. Cardiff University; Reino UnidoFil: Engel, Christoph. European Hereditary Tumour Group; Reino Unido. Universitat Leipzig; AlemaniaFil: Aretz, Stefan. Universitat Bonn; AlemaniaFil: Jenkins, Mark A.. University of Melbourne; AustraliaFil: Sunde, Lone. Aalborg University; DinamarcaFil: Bernstein, Inge. Aalborg University; DinamarcaFil: Capella, Gabriel. European Hereditary Tumour Group; Reino Unido. St Mark’s Hospital; Reino Unido. Institut Català d’Oncologia; EspañaFil: Balaguer Prunés, Francesc. Universidad de Barcelona; EspañaFil: Macrae, Finlay. European Hereditary Tumour Group; Reino Unido. The Royal Melbourne Hospital; AustraliaFil: Winship, Ingrid M.. University of Melbourne; AustraliaFil: Thomas, Huw. Imperial College London; Reino UnidoFil: Evans, Dafydd Gareth. University of Manchester; Reino UnidoFil: Burn, John. Universidad de Newcastle; Australia. The Royal Melbourne Hospital; Australia. St Mark’s Hospital; Reino UnidoFil: Greenblatt, Marc. University of Vermont; Estados UnidosFil: de Vos tot Nederveen Cappel, Wouter H.. Isala Clinics; Países BajosFil: Sijmons, Rolf H.. University of Groningen; Países Bajos. St Mark’s Hospital; Reino Unido. European Hereditary Tumour Group; Reino UnidoFil: Nielsen, Maartje. Leids Universitair Medisch Centrum; Países BajosFil: Bertario, Lucio. Fondazione IRCCS Istituto Nazionale dei Tumori; ItaliaFil: Bonanni, Bernardo. Fondazione IRCCS Istituto Nazionale dei Tumori; ItaliaFil: Tibiletti, Maria Grazia. Università dell’Insubria; ItaliaFil: Cavestro, Giulia Martina. Vita-Salute San Raffaele University; ItaliaFil: Lindblom, Annika. Karolinska Huddinge Hospital; SueciaFil: Della Valle, Adriana. Hospital Fuerzas Armadas; UruguayFil: Lopez Kostner, Francisco. Clínica Universidad de los Andes; ChileFil: Alvarez, Karin. Clínica Universidad de los Andes; ChileFil: Gluck, Nathan. Universitat Tel Aviv; IsraelFil: Katz, Lior. Sheba Medical Center; IsraelFil: Heinimann, Karl. University Hospital Basel; SuizaFil: Piñero, Tamara Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; ArgentinaFil: Pavicic, Walter Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; Argentin

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2:A Prospective Lynch Syndrome Database Study

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2

Uptake of hysterectomy and bilateral salpingooophorectomy in carriers of pathogenic mismatch repair variants:a Prospective Lynch Syndrome Database report

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants. Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years. Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery. Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants:findings from the Prospective Lynch Syndrome Database

Purpose Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. Methods We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. Results There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers

Germline MBD4-deficiency causes a multi-tumor predisposition syndrome

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management