Cancer predisposition

Lynch syndrome (LS) is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR) genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS) must be defined...

Despite the growing knowledge of the genetic background behind the cancers that occur in a context of hereditary predisposition, personal or family cancer history may not be clear enough to support directional gene testing. Defined targeted next-generation sequencing gene panels allow identification of the causative disease mutations of multigene syndromes and differential diagnosis for syndromes with phenotypically overlapping characteristics. Herein, we established a next-generation sequencing analysis pipeline for the molecular diagnosis of multiple inherited cancer predisposing syndromes using the commercially available target sequencing panel TruSight Cancer...

Lynch Syndrome (LS) is the most common dominantly inherited colorectal cancer (CRC) predisposition and is caused by a heterozygous germline defect in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. High microsatellite instability (MSI-H) and loss of MMR protein expression in tumours reflecting a defective MMR are indicators for LS, as well as a positive family history of early onset CRC. MSH2 and MSH6 form a major functional heterodimer, and MSH3 is an alternative binding partner for MSH2...

Xeroderma pigmentosum complementation group A (XP-A) is a hereditary disease characterized by early onset of skin cancers and freckles-like pigmented maculae in the sun-exposed sites. Although etiology of predisposition to UV-induced skin tumors in XP-A is well investigated as a repair deficiency in UV-induced DNA damage, the mechanism of exaggerated sunburn in patients with XP-A and whether UV-induced inflammation relates to skin tumor-prone phenotype remains to be elucidated. Using gene profiling of XP-A model mice, Xpa-deficient mice, we found that expression of CXCL1 in the skin and blood levels of in Xpa-deficient mice increased significantly after UVB exposure at an even a limited area in comparison to those of wild-type mice...

BACKGROUND: The growing number of Next Generation Sequencing (NGS) tests is transforming the routine clinical diagnosis of hereditary cancers. Identifying whether a cancer is the result of an underlying disease-causing mutation in a cancer predisposition gene is not only diagnostic for a cancer predisposition syndrome, but also has significant clinical implications in the clinical management of patients and their families. METHODS: Here, we evaluated the performance of MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) in detecting genetic alterations in 76 genes implicated in cancer predisposition syndromes...

Low-grade gliomas are one of the most common brain tumors in children, where they frequently form within the optic pathway (optic pathway gliomas; OPGs). Since many OPGs occur in the context of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome, we have previously employed Nf1 genetically-engineered mouse (GEM) strains to study the pathogenesis of these low-grade glial neoplasms. In the light of the finding that human and mouse low-grade gliomas are composed of Olig2+ cells and that Olig2+ oligodendrocyte precursor cells (OPCs) give rise to murine high-grade gliomas, we sought to determine whether Olig2+ OPCs could be tumor-initiating cells for Nf1 optic glioma...

INTRODUCTION: Long interspersed element (LINE)-1 (L1) is a type of retrotransposon capable of mobilizing into new genomic locations. Often studied in Mendelian diseases or cancer, L1s may also cause somatic mutation in the developing central nervous system. Recent reports showed L1 transcription was activated in brains of cocaine-treated mice, and L1 retrotransposition was increased in cocaine-treated neuronal cell cultures. We hypothesized that the predisposition to cocaine addiction may result from inherited L1s or somatic L1 mobilization in the brain...

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BACKGROUND: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p...

BACKGROUND: Multiple environmental exposures may derange the regulatory and repair mechanisms of the skin and lead to dermatological disease. OBJECTIVES: Provide an overview of non-allergic skin diseases associated with environmental factors. MATERIALS AND METHODS: Review of current scientific evidence for associations of non-allergic skin diseases with environmental exposures: irritation, chemicals, infection, UV-radiation, temperature. RESULTS: Predisposition (constitution e...

There are no regulations in the Netherlands regarding the exchange of important genetic information that has become available after the birth of a child conceived with donor gametes. This may lead to difficult situations such as when the gamete donor is found to suffer from a genetic cancer-predisposition disorder. Genetic information about the donor that becomes available later may be of great importance to donor offspring. Genetic information uncovered in the donor child may likewise be of importance to legal offspring of the gamete donor...

RAD51 is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant-negative mutations. FA is a hereditary DNA-repair disorder characterized by various congenital abnormalities, progressive bone marrow failure, and cancer predisposition. In this report, we describe a viable vertebrate model of RAD51 loss. Zebrafish rad51 loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to cross-linking agents, and decreased size...

CONTEXT: A number of single nucleotide polymorphisms (SNPs) in ERBB4 gene have been linked to increase the risk of breast cancer. However, no study has been dedicated to analyze the significance of microRNA-related SNP rs1972820, located in ERBB4 3'-untranslated region (UTR), in breast tumors. AIMS: Here, we investigated the frequency and association between rs1972820 and breast cancer. SUBJECTS AND METHODS: The rs1972820 genotypes in 182 samples were collected from 96 healthy people, and 86 breast cancer patients were determined using tetra-primer amplification refractory mutation system-polymerase chain reaction...

Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome accounting for approximately 1000 cases of colorectal cancer (CRC) in the UK annually. LS is characterised by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. The penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether low penetrance genetic risk factors may result in phenotype modification in LS patients. To conduct a systematic literature review and meta-analysis to assess the association between low penetrance genetic risk modifiers and CRC in LS patients...

Glioblastoma (GBM) is resistant to most multimodal therapies. Clinical success of immune-checkpoint inhibitors (ICIs) has spurred interest in applying ICIs targeting CTLA4, PD1 or IDO1 against GBM. This amplifies the need to ascertain GBM's intrinsic susceptibility (or resistance) toward these ICIs, through clinical biomarkers that may also "guide and prioritize" preclinical testing. Here, we interrogated the TCGA and/or REMBRANDT human patient-cohorts to predict GBM's predisposition toward ICIs. We exploited various broad clinical biomarkers, including mutational or predicted-neoantigen burden, pre-existing or basal levels of tumor-infiltrating T lymphocytes (TILs), differential expression of immune-checkpoints within the tumor and their correlation with particular TILs/Treg-associated functional signature and prognostic impact of differential immune-checkpoint expression...

The respiratory chain Complex I deficiencies are the most common cause of mitochondrial diseases. Complex I biogenesis is controlled by 58 genes and at least 47 of these cause mitochondrial disease in humans. Two of these are X-chromosome linked nuclear (nDNA) genes (NDUFA1 and NDUFB11), and 7 are mitochondrial (mtDNA, MT-ND1-6, 4L) genes, which may be responsible for sex-dependent variation in the presentation of mitochondrial diseases. In this study, we describe an X-chromosome linked mouse model (Ndufa1(S55A)) for systemic partial Complex I deficiency...

Constitutional mismatch repair deficiency (CMMRD) is a rare, recessively inherited childhood cancer predisposition syndrome caused by bi-allelic germline mutations in one of the mismatch repair genes. The CMMRD phenotype overlaps with that of neurofibromatosis type 1 (NF1), since many patients have multiple café-au-lait macules (CALM) and other NF1 signs, but no germline NF1 mutations. We report of a case of a healthy six-year-old girl who fulfilled the diagnostic criteria of NF1 with >6 CALM and freckling...

PURPOSE: Although breast cancer in young women accounts for <10% of diagnoses annually, tumors in young patients exhibit more aggressive characteristics and higher mortality rates. Determination of the frequency of germline mutations in cancer predisposition genes is needed to improve the understanding of breast cancer etiology in young women. METHODS: All female patients enrolled in the Clinical Breast Cancer Project between 2001 and 2015 and diagnosed with invasive breast cancer before age 40 were included in this study...

Identification of genetic alterations is important for family risk assessment in colorectal cancers. Next-generation sequencing (NGS) technologies provide useful tools for single-nucleotide and copy number variation (CNV) identification in many genes and samples simultaneously. Herein, we present the validation of current Multiplicom MASTR designs of mismatch repair combined to familial adenomatous polyposis genes in a single PCR reamplification test for eight DNA samples simultaneously on a MiSeq apparatus...

Breast cancer is predicted to be the most common newly diagnosed cancer in women in 2016. Screening mammography is the most commonly used method for the detection of breast cancer in women of average risk. A genetic risk assessment is recommended for women with a greater than 20% to 25% chance of having a predisposition to breast and ovarian cancer. Evaluation of a breast mass begins with a detailed history, assessment for cancer risk, and physical examination.