The apparent genetic anticipation in PMS2-associated Lynch syndrome families is explained by birth cohort effect

BACKGROUND: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families. METHODS: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias. RESULTS: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively]. CONCLUSIONS: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome. IMPACT: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition

A heritable form of SMARCE1-related meningiomas with important implications for follow-up and family screening.

Childhood meningiomas are rare. Recently, a new hereditary tumor predisposition syndrome has been discovered, resulting in an increased risk for spinal and intracranial clear cell meningiomas (CCMs) in young patients. Heterozygous loss-of-function germline mutations in the SMARCE1 gene are causative, giving rise to an autosomal dominant inheritance pattern. We report on an extended family with a pediatric CCM patient and an adult CCM patient and several asymptomatic relatives carrying a germline SMARCE1 mutation, and discuss difficulties in genetic counseling for this heritable condition. Because of the few reported cases so far, the lifetime risk of developing meningiomas for SMARCE1 mutation carriers is unclear and the complete tumor spectrum is unknown. There is no surveillance guideline for asymptomatic carriers nor a long-term follow-up recommendation for SMARCE1-related CCM patients as yet. Until more information is available about the penetrance and tumor spectrum of the condition, we propose the following screening advice for asymptomatic SMARCE1 mutation carriers: neurological examination and MRI of the brain and spine, yearly from diagnosis until the age of 18 and once every 3 years thereafter, or in between if there are clinical symptoms. This advice can also be used for long-term patient follow-up. More data is needed to optimize this proposed screening advice

Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane-protein-127 (TMEM127) is one of the PCC/PGL-susceptibility genes with an autosomal dominant inheritance pattern. Here, we report 2 patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year-old mentally retarded patient, the homozygous c.410-2A > G mutation was discovered during an update of DNA analysis. A 26-year-old mentally retarded patient was found to have a homozygous c.3G > A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127 mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC-susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127 mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrine concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127 mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information

Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations:Case series, review and follow-up guidelines

BACKGROUND: Bi-allelic germline mutations of one of the DNA mismatch repair genes, so far predominantly found in PMS2, cause constitutional MMR-deficiency syndrome. This rare disorder is characterised by paediatric intestinal cancer and other malignancies. We report the clinical, immunohistochemical and genetic characterisation of four families with bi-allelic germline PMS2 mutations. We present an overview of the published gastrointestinal manifestations of CMMR-D syndrome and propose recommendations for gastro-intestinal screening. METHODS AND RESULTS: The first proband developed a cerebral angiosarcoma at age 2 and two colorectal adenomas at age 7. Genetic testing identified a complete PMS2 gene deletion and a frameshift c.736_741delinsTGTGTGTGAAG (p.Pro246CysfsX3) mutation. In the second family, both the proband and her brother had multiple intestinal adenomas, initially wrongly diagnosed as familial adenomatous polyposis. A splice site c.2174+1G>A, and a missense c.137G>T (p.Ser46Ile) mutation in PMS2 were identified. The third patient was diagnosed with multiple colorectal adenomas at age 11; he developed a high-grade dysplastic colorectal adenocarcinoma at age 21. Two intragenic PMS2 deletions were found. The fourth proband developed a cerebral anaplastic ganglioma at age 9 and a high-grade colerectal dysplastic adenoma at age 10 and carries a homozygous c.2174+1G>A mutation. Tumours of all patients showed microsatellite instability and/or loss of PMS2 expression. CONCLUSIONS: Our findings show the association between bi-allelic germline PMS2 mutations and severe childhood-onset gastrointestinal manifestations, and support the notion that patients with early-onset gastrointestinal adenomas and cancer should be investigated for CMMR-D syndrome. We recommend yearly follow-up with colonoscopy from age 6 and simultaneous video-capsule small bowel enteroscopy from age 8

საქართველოს სოციალისტური საბჭოთა რესპუბლიკის მუშათა და გლეხთა მთავრობის კანონთა და განკარგულებათა კრებული N16

Introduction: Recognising a tumour predisposition syndrome (TPS) in childhood cancer patients is of major clinical relevance. The presence of a TPS may be suggested by the type of tumour in the child. We present an overview of 23 childhood tumours that in themselves should be a reason to refer a child for genetic consultation. Methods: We performed a PubMed search to review the incidence of TPSs in children for 85 tumour types listed in the International Classification of Childhood Cancer third edition (ICCC-3). The results were discussed during a national consensus meeting with representative clinical geneticists from all six academic paediatric oncology centres in The Netherlands. A TPS incidence of 5% or more was considered a high probability and therefore in itself a reason for referral to a clinical geneticist. Results: The literature search resulted in data on the incidence of a TPS in 26 tumours. For 23/26 tumour types, a TPS incidence of 5% or higher was reported. In addition, during the consensus meeting the experts agreed that children with any carcinoma should always be referred for clinical genetic consultation as well, as it may point to a TPS. Conclusion: We present an overview of 23 paediatric tumours with a high probability of a TPS; this will facilitate paediatric oncologists to decide which patients should be referred for genetic consultation merely based on type of tumour. (C) 2017 Elsevier Ltd. All rights reserved

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers

PURPOSE: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype. METHODS: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally. RESULTS: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC. CONCLUSIONS: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med advance online publication 25 June 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.83

Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2

Background & Aims: Germline variants in mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in older patients than CRCs with variants in other mismatch repair genes. Methods: We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3,000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher exact test. Results: None of the PMS2-associated CRCs contained any somatic variants in the catenin-β1 gene (CTNNB1), which encodes β-catenin, whereas 14 of 24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half the PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%; P =.44) and MSH2 (71.4%; P =.035) than in those associated with variants in PMS2. Conclusions: In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence

Nonfilling Carbon Coating of Porous Silicon Micrometer-Sized Particles for High-Performance Lithium Battery Anodes

Silicon is widely recognized as one of the most promising anode materials for lithium-ion batteries due to its 10 times higher specific capacity than graphite. Unfortunately, the large volume change of Si materials during their lithiation/delithiation process results in severe pulverization, loss of electrical contact, unstable solid–electrolyte interphase (SEI), and eventual capacity fading. Although there has been tremendous progress to overcome these issues through nanoscale materials design, improved volumetric capacity and reduced cost are still needed for practical application. To address these issues, we design a nonfilling carbon-coated porous silicon microparticle (nC-pSiMP). In this structure, porous silicon microparticles (pSiMPs) consist of many interconnected primary silicon nanoparticles; only the outer surface of the pSiMPs was coated with carbon, leaving the interior pore structures unfilled. Nonfilling carbon coating hinders electrolyte penetration into the nC-pSiMPs, minimizes the electrode–electrolyte contact area, and retains the internal pore space for Si expansion. SEI formation is mostly limited to the outside of the microparticles. As a result, the composite structure demonstrates excellent cycling stability with high reversible specific capacity (∼1500 mAh g^–1, 1000 cycles) at the rate of C/4. The nC-pSiMPs contain accurate void space to accommodate Si expansion while not losing packing density, which allows for a high volumetric capacity (∼1000 mAh cm^–3). The areal capacity can reach over 3 mAh cm^–2 with the mass loading 2.01 mg cm^–2. Moreover, the production of nC-pSiMP is simple and scalable using a low-cost silicon monoxide microparticle starting material