Attitudes Toward Updated Genetic Testing Among Patients with Unexplained Mismatch Repair Deficiency

Individuals who have colorectal cancer (CRC) or endometrial cancer (EC) displaying loss of immunohistochemical (IHC) staining of one or more mismatch repair (MMR) proteins without a causative germline mutation are said to have unexplained mismatch repair deficiency (UMMRD, also known as mutation-negative Lynch syndrome). Comprehensive genetic testing that could potentially further clarify Lynch syndrome (LS) carrier status is essential to provide tailored screening guidelines to affected individuals and their family members; however, patient understanding of the potential impact of updated genetic testing for LS is unclear. This study aimed to evaluate the interest in and perceived impact of updated genetic testing among individuals with UMMRD at a tertiary academic center. A survey evaluating interest in updated genetic testing was mailed to 98 potential participants, and an electronic health record review was completed for the 31 individuals who returned the survey. Results indicate that this population is highly interested in updated genetic testing, and their perceived impact is primarily for family members to have appropriate testing and screening options. Updated risk assessment and genetic counseling, along with a discussion of the benefits and limitations of genetic testing, is essential as the understanding of potential causes of UMMRD evolves. Updated genetic counseling may allow patients with UMMRD to better understand the interpretation of their tumor and germline testing, as well as the impact of comprehensive genetic testing for themselves and their family members

Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas.

Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. Genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM

CANCER: A MOLECULAR CURSE?

Cancer is one of the most common causes of death, taking over 7 million lives each year globally. The global incidence is remarkably rising. Massive investments in research are also on the rise to unravel the genetic and molecular basis of cancer as a prerequisite to design of more effective treatment strategies. This review explores causes of cancer, its molecular basis and the treatment strategies. Future perspectives regarding research on cancer and envisaged milestones of management and/or treatment interventions are also explored

Ageing And Cancer As Diseases Of Epigenesis

Cancer and ageing are often said to be diseases of development. During the past fifty years, the genetic components of cancer and ageing have been intensely investigated since development, itself, was seen to be an epiphenomenon of the genome. However, as we have learned more about the expression of the genome, we find that differences in expression can be as important as differences in alleles. It is easier to inactivate a gene by methylation than by mutation, and given that appropriate methylation is essential for normal development, one can immediately see that diseases would result as a consequence of inappropriate epigenetic methylation. While first proposed by Boris Vanyushin in 1973, recent studies have confirmed that inappropriate methylation not only causes diseases, and it also may be the critical factor in ageing and cancers

Family Matters: Adjustment to genetic cancer susceptibility testing

Cancer is generally feared because it is associated with death and severe physical suffering. It is one of the most common causes of death in the Netherlands. Breast and colon cancer are the most prevalent types of cancer among women. Frequently occurring types in men are cancer of colon, lung and prostate. About 5% of colorectal and breast cancer arises as a result of a mutation in an inherited cancer susceptibility gene. Knowledge about these cancer susceptibility genes has been accumulating in an impressive manner over the last decades, resulting in the clinical availability of genetic testing from the mid-nineties onward. Through genetic testing, an individual’s risk to develop cancer can be determined more precisely. This can reduce feelings of uncertainty about the r

Pathway relevance ranking for tumor samples through network-based data integration

The study of cancer, a highly heterogeneous disease with different causes and clinical outcomes, requires a multi-angle approach and the collection of large multi-omics datasets that, ideally, should be analyzed simultaneously. We present a new pathway relevance ranking method that is able to prioritize pathways according to the information contained in any combination of tumor related omics datasets. Key to the method is the conversion of all available data into a single comprehensive network representation containing not only genes but also individual patient samples. Additionally, all data are linked through a network of previously identified molecular interactions. We demonstrate the performance of the new method by applying it to breast and ovarian cancer datasets from The Cancer Genome Atlas. By integrating gene expression, copy number, mutation and methylation data, the method's potential to identify key pathways involved in breast cancer development shared by different molecular subtypes is illustrated. Interestingly, certain pathways were ranked equally important for different subtypes, even when the underlying (epi)-genetic disturbances were diverse. Next to prioritizing universally high-scoring pathways, the pathway ranking method was able to identify subtype-specific pathways. Often the score of a pathway could not be motivated by a single mutation, copy number or methylation alteration, but rather by a combination of genetic and epi-genetic disturbances, stressing the need for a network-based data integration approach. The analysis of ovarian tumors, as a function of survival-based subtypes, demonstrated the method's ability to correctly identify key pathways, irrespective of tumor subtype. A differential analysis of survival-based subtypes revealed several pathways with higher importance for the bad-outcome patient group than for the good-outcome patient group. Many of the pathways exhibiting higher importance for the bad-outcome patient group could be related to ovarian tumor proliferation and survival

NGS Panels applied to Hereditary Cancer Syndromes

Cancer is among the leading causes of morbidity and mortality worldwide (Okur et al, 2017). Germline pathogenic variants for monogenic, highly penetrant cancer susceptibility genes are observed in 5%–10% of all cancers (Lu et al, 2014). Hereditary cancers due to monogenic causes are characterized by earlier age of onset, other associated cancers, and often a family history of specific cancers. From the clinical perspective, it is important to recognize the affected individuals to provide them the best clinical management (Hennessy et al, 2010; Ledermann et al, 2014; Pennington et al, 2014) and to identify at-risk family members who will benefit from predictive genetic testing and enhanced surveillance, including early detection and/or risk reduction measures (Kurian et al, 2010; Okur et al, 2017). Germline variants identified in major cancer susceptibility genes associated with hereditary breast or ovarian cancer (HBOC) or hereditary colorectal cancer (HCRC), also account for 5-10% of the patients with these cancers. In the last years, new susceptibility genes, with different penetrance degrees, have been identified. Variants in any of those genes are rare and classical methodologies (e.g. Sanger sequencing - SS) are time consuming and expensive. Next-generation sequencing (NGS) has several advantages compared to SS, including the simultaneous analysis of many samples and sequencing of a large set of genes, higher sensitivity (down to 1% vs 15-20% in SS), lower cost and faster turnaround time, reasons that make NGS the best approach for molecular diagnosis. It is possible nowadays to choose between whole-genome sequencing (WGS), whole-exome sequencing (WES) and NGS limited to a set of genes (NGS-Panel). In cases where a suspected genetic disease or condition has been identified, targeted sequencing of specific genes or genomic regions is preferred (Grada et al, 2013). For that reason, we use NGS-Panel approach using TruSight Cancer (Illumina) to sequence DNA extracted from blood samples of patients with personal and/or familiar history of cancer. This hereditary cancer gene panel sequences 94 genes associated with both common (e.g., breast, colorectal) and rare hereditary cancers and allows the creation of virtual gene panels according to each phenotype or disease under study. NGS workflow analysis (Figure 1) includes five steps: quality assessment of raw data, read alignment to a reference genome, variant identification/calling, variant annotation and data visualization (Pabinger et al, 2013). The establishment of the most appropriate bioinformatics pipeline is crucial in order to achieve the best results. NGS data allows the identification of several types of variants like single nucleotide variants (SNVs), small insertions/deletions, inversions and also copy number variants (CNVs).FCT - UID/BIM/0009/2016info:eu-repo/semantics/publishedVersio

A Literature Resource for Those Supporting Patients with Autism Spectrum Disorder and Cancer

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that impacts both social interaction and patterns of behavior. ASD is rooted in genetic, biological, and environmental causes. Cancer begins when cells grow out of control and there is also a genetic and biological cause of cancer. There is an overlap between the genetic and biological causes of ASD and cancer. As a result, evidence supports an increased risk of developing some types of cancer as well as protective factors for some times of cancer for individuals with ASD. Therefore, individuals with ASD may be at a heightened risk to develop cancer, but ASD specialists are not often well versed in the procedures that occur when treating cancer. Further, professionals treating cancer may not be familiar with the symptoms and challenges that may be present when treating someone on the autism spectrum. The possibility for a patient to develop trauma symptoms related to experiences with cancer and cancer treatment and the unique characteristics of treating someone with ASD, trauma, and cancer is explored. In addition, caregivers are not often prepared for a comorbid cancer diagnosis that may accompany ASD. Obtaining this kind of specialized knowledge could be significantly beneficial when supporting an individual with ASD through a cancer diagnosis and treatment. As a result, the present product aims to provide evidence based supportive knowledge to caregivers, psychologists, medical health professionals, and other personnel who may be actively working with an individual who has autism and cancer or who is interested in gaining more knowledge about the relationship between autism and cancer

How to target apoptosis signaling pathways for the treatment of pediatric cancers

Apoptosis represents one of the most important forms of cell death in higher organisms and is typically dysregulated in human cancers, including pediatric tumors. This implies that ineffective engagement of cell death programs can contribute to tumor formation as well as tumor progression. In addition, the majority of cytotoxic therapeutic principles rely on the activation of cell death signaling pathways in cancer cells. Blockade of signaling networks that lead to cell death can therefore confer treatment resistance. A variety of genetic and epigenetic events as well as dysfunctional regulation of signaling networks have been identified as underlying causes of cell death resistance in childhood malignancies. Apoptosis pathways can be therapeutically exploited by enhancing proapoptotic signals or by neutralizing antiapoptotic programs. The challenge in the coming years will be to successfully transfer this knowledge into the development of innovative treatment approaches for children with cancer