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Lynch syndrome (LS), caused by heterozygous germline mutation in one of the key mismatch repair (MMR) genes, is the primary cause of inherited colorectal cancer (CRC). LS also increases susceptibility to several other cancers. It is estimated that just 5% of patients with LS are aware of their diagnosis. Therefore, in an attempt to increase the identification of cases within the UK population, the 2017 NICE guidelines recommend offering immunohistochemistry for MMR proteins or microsatellite instability (MSI) testing to all people with CRC when first diagnosed. Following identification of MMR deficiency, eligible patients should be assessed for underlying causes, including potential referral to the genetics service and/or germline LS testing (if appropriate). In our regional centre for CRC, we audited local pathways to identify what proportion of patients are being correctly referred, in line with national guidelines. Reflecting on these results, we highlight our practical concerns by identifying the pitfalls and issues faced with the recommended referral pathway. We also propose possible solutions to improve the efficacy of the system for both referrers and patients. Finally, we discuss the ongoing interventions that national bodies and regional centres are implementing to improve and further streamline this process. [ABSTRACT FROM AUTHOR]

Abstract Background Hereditary Diffuse Gastric Cancer (HDGC) syndrome is an autosomal dominant hereditary cancer predisposition associated with germline pathogenic/likely pathogenic variants in the CDH1 gene. Identifying early stage HDGC is difficult, and prophylactic measures can be effective in preventing incidence. Preimplantation Genetic Testing (PGT) can provide information about CDH1 variant status, HDGC risk, and limit familial transmission of CDH1 variants. To date, however, little is known about the attitudes of individuals with CDH1 variants towards PGT. Methods Given that little is known about the reproductive attitudes of individuals with HDGC, we recruited participants with CDH1 variants from a familial gastric cancer registry and administered a cross-sectional survey with open- and closed-ended response items. We assessed attitudes regarding PGT and the effect of HDGC on quality of life. Results Participants (n = 21) were predominantly partnered (61.9%), had a personal cancer history (71.4%), and had biological children (71.4%). Interest in learning about PGT was high; 66.7% of participants were interested in PGT and 90.5% approved of healthcare providers discussing PGT with individuals with CDH1 variants. Attitudes regarding personal use were varied. Among all participants, 35% would not, 25% were uncertain, and 40% would use PGT. Personal philosophy and preferences for family and reproduction were key factors related to PGT attitudes. HDGC had moderate effects on participants’ quality of life, including social relationships, health behaviors, and emotional experiences including worry about cancer risk and guilt regarding familial implications. Conclusion PGT was identified by participants as acceptable for use in a variety of contexts and benefits of reproductive counseling involving PGT may extend beyond CDH1 carriers to family members’ reproductive behaviors. Dispositions towards PGT are governed by personal philosophy or belief systems. These findings can help guide providers counseling individuals with CDH1 variants.

The tumors of central nervous system refer to a group of benign and malignant diseases originating from tissues or structures within the central nervous system. Common tumors of central nervous system are sporadic, but a few have familial onset. Compared with sporadic brain tumors, the clinical symptoms, diagnostic ideas and follow-up review plans of familial brain tumors are more complicated. The multidisciplinary diagnosis and treatment (MDT) mode usually refers to a treatment mode in which a case involving multiple organs and systems is discussed, and the best treatment plan is formulated for the patient based on the comprehensive opinions of various disciplines. Because familial brain tumors often involve multiple organs, multiple disciplines and multiple systems, and their low incidence leads to less clinical experience for neurosurgeons, the MDT model is more conducive to efficient diagnosis, treatment and management of familial brain tumors. This review elaborates on the neurosurgeon-led MDT model, and introduces the latest research on the epidemiology, genetic characteristics, clinical manifestations, diagnostic ideas and multidisciplinary management of familial brain tumors.

Background: Hereditary Diffuse Gastric Cancer (HDGC) syndrome is an autosomal dominant hereditary cancer predisposition associated with germline pathogenic/likely pathogenic variants in the CDH1 gene. Identifying early stage HDGC is difficult, and prophylactic measures can be effective in preventing incidence. Preimplantation Genetic Testing (PGT) can provide information about CDH1 variant status, HDGC risk, and limit familial transmission of CDH1 variants. To date, however, little is known about the attitudes of individuals with CDH1 variants towards PGT. Methods: Given that little is known about the reproductive attitudes of individuals with HDGC, we recruited participants with CDH1 variants from a familial gastric cancer registry and administered a cross-sectional survey with open- and closed-ended response items. We assessed attitudes regarding PGT and the effect of HDGC on quality of life. Results: Participants (n = 21) were predominantly partnered (61.9%), had a personal cancer history (71.4%), and had biological children (71.4%). Interest in learning about PGT was high; 66.7% of participants were interested in PGT and 90.5% approved of healthcare providers discussing PGT with individuals with CDH1 variants. Attitudes regarding personal use were varied. Among all participants, 35% would not, 25% were uncertain, and 40% would use PGT. Personal philosophy and preferences for family and reproduction were key factors related to PGT attitudes. HDGC had moderate effects on participants' quality of life, including social relationships, health behaviors, and emotional experiences including worry about cancer risk and guilt regarding familial implications. Conclusion: PGT was identified by participants as acceptable for use in a variety of contexts and benefits of reproductive counseling involving PGT may extend beyond CDH1 carriers to family members' reproductive behaviors. Dispositions towards PGT are governed by personal philosophy or belief systems. These findings can help guide providers counseling individuals with CDH1 variants. [ABSTRACT FROM AUTHOR]

The tumors of central nervous system refer to a group of benign and malignant diseases originating from tissues or structures within the central nervous system. Common tumors of central nervous system are sporadic, but a few have familial onset. Compared with sporadic brain tumors, the clinical symptoms, diagnostic ideas and follow-up review plans of familial brain tumors are more complicated. The multidisciplinary diagnosis and treatment (MDT) mode usually refers to a treatment mode in which a case involving multiple organs and systems is discussed, and the best treatment plan is formulated for the patient based on the comprehensive opinions of various disciplines. Because familial brain tumors often involve multiple organs, multiple disciplines and multiple systems, and their low incidence leads to less clinical experience for neurosurgeons, the MDT model is more conducive to efficient diagnosis, treatment and management of familial brain tumors. This review elaborates on the neurosurgeon-led MDT model, and introduces the latest research on the epidemiology, genetic characteristics, clinical manifestations, diagnostic ideas and multidisciplinary management of familial brain tumors. [ABSTRACT FROM AUTHOR]

This study demonstrates that germline mutations in the TP53 gene are likely to predispose men to prostate cancer. Current Li-Fraumeni syndrome screening guidelines should be updated to consider annual prostate cancer screening, and TP53 should be considered in germline prostate cancer susceptibility testing. Inherited germline TP53 pathogenic and likely pathogenic variants (g TP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53. To determine whether gTP53 predisposes to prostate cancer. This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and g TP53 prevalence in a prostate cancer cohort. We evaluated the spectrum of g TP53 variants and clinical features associated with prostate cancer. We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3–7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2–55; p < 0.0001). We identified g TP53 in 38 of 6850 males (0.6%) in the prostate cancer cohort, a relative risk 9.1-fold higher than that of population controls (95% CI 6.2–14; p < 0.0001; gnomAD). We observed hotspots at the sites of attenuated variants not associated with classic LFS. Two-thirds of available g TP53 prostate tumors had somatic inactivation of the second TP53 allele. Among g TP53 prostate cancer cases in this study, the median age at diagnosis was 56 (IQR: 51–62) yr, 44% had Gleason ≥8 tumors, and 29% had advanced disease at diagnosis. Complementary analyses of prostate cancer incidence in LFS males and g TP53 prevalence in prostate cancer cohorts suggest that g TP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing. Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer. [ABSTRACT FROM AUTHOR]

Fifteen to 20% of children with neurofibromatosis type 1 develop low-grade glial neoplasms. However, since neuroimaging is not routinely obtained until a child is clinically symptomatic, little is known about presymptomatic radiographic characteristics of gliomas in this at-risk population. Herein, we describe a child with neurofibromatosis type 1 who initially had normal brain imaging before the development of multifocal gliomas. Comparison of these serial images demonstrated that brain tumors can arise de novo in children with this cancer predisposition syndrome, further underscoring the limited prognostic value of normal baseline magnetic resonance imaging.

Next-generation sequencing (NGS) technology has expanded in the last decades with significant improvements in the reliability, sequencing chemistry, pipeline analyses, data interpretation and costs. Such advances make the use of NGS feasible in clinical practice today. This review describes the recent technological developments in NGS applied to the field of oncology. A number of clinical applications are reviewed, i.e., mutation detection in inherited cancer syndromes based on DNA-sequencing, detection of spliceogenic variants based on RNA-sequencing, DNA-sequencing to identify risk modifiers and application for pre-implantation genetic diagnosis, cancer somatic mutation analysis, pharmacogenetics and liquid biopsy. Conclusive remarks, clinical limitations, implications and ethical considerations that relate to the different applications are provided. [ABSTRACT FROM AUTHOR]

Cancer risks in heterozygous mutation carriers of the ATM, BLM, and FANCC genes are controversial. To shed light on this issue, cancer rates were evaluated by cross referencing asymptomatic Israeli heterozygous mutation carriers in the ATM, BLM, and FANCC genes with cancer diagnoses registered at the Israeli National Cancer Registry (INCR). Comparison of observed to expected Standardized Incidence Rates (SIR) was performed. Overall, 474 individuals participated in the study: 378 females; 25 Arab and 31 Jewish ATM carriers, 152 BLM carriers, and 170 FANCC carriers (all Ashkenazim). Age range at genotyping was 19–53 years (mean + SD 30.6 + 5 years). In addition, 96 males were included; 5, 34, and 57 ATM, BLM, and FANCC mutation carriers, respectively. Over 5–16 years from genotyping (4721 person/years), 15 new cancers were diagnosed in mutation carriers: 5 breast, 4 cervical, 3 melanomas, and one each bone sarcoma, pancreatic, and colorectal cancer. No single cancer diagnosis was more prevalent then expected in all groups combined or per gene analyzed. Specifically breast cancer SIR was 0.02–0.77. We conclude that Israeli ATM, BLM, and FANCC heterozygous mutation carriers are not at an increased risk for developing cancer. [ABSTRACT FROM AUTHOR]

Molecular epidemiology is the study of genetic and environmental risk for disease, with much effort centered on cancer. Childhood leukemia occurs in nearly a third of all patients newly diagnosed with pediatric cancer. only a small percentage of these new cases of childhood leukemia are associated with high penetrant hereditary cancer syndromes. Childhood leukemia, especially acute lymphoblastic leukemia, has been associated with a dysregulated immune system due to delayed infectious exposure at a young age. Identical twins with childhood leukemia suggest that acute lymphoblastic leukemia begins in utero and that the concordant presentation is due to a shared preleukemia subclone via placental transfer. Investigation of single nucleotide polymorphisms within candidate genes find that leukemia risk may be attributed to population-based polymorphisms affecting folate metabolism, xenobiotic metabolism, DNA repair, immunity, and B-cell development. More recently, genome-wide association studies for leukemia risk has led investigators to genes associated with B-cell development. When describing leukemia predisposition due to hereditary cancer syndromes, the following 6 categories become apparent on the basis of biology and clinical presentation: (1) genetic instability/DNA repair syndromes, (2) cell cycle/differentiation syndromes, (3) bone marrow failure syndromes, (4) telomere maintenance syndromes, (5) immunodeficiency syndromes, and (6) transcription factor syndromes and pure familial leukemia. understanding the molecular epidemiology of childhood leukemia can affect the treatment and tumor surveillance strategies for these high risk patients and their family members. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) technology has expanded in the last decades with significant improvements in the reliability, sequencing chemistry, pipeline analyses, data interpretation and costs. Such advances make the use of NGS feasible in clinical practice today. This review describes the recent technological developments in NGS applied to the field of oncology. A number of clinical applications are reviewed, i.e., mutation detection in inherited cancer syndromes based on DNA-sequencing, detection of spliceogenic variants based on RNA-sequencing, DNA-sequencing to identify risk modifiers and application for pre-implantation genetic diagnosis, cancer somatic mutation analysis, pharmacogenetics and liquid biopsy. Conclusive remarks, clinical limitations, implications and ethical considerations that relate to the different applications are provided.

Children with neurofibromatosis type 1 are at increased risk for the development of attention problems relative to their unaffected peers. Previous studies have reported deficits in sustained auditory attention, but other aspects of attention, including sustained visual attention, divided attention, response inhibition, and selective attention, have not been consistently documented. In the present study, we specifically investigated attention skills in children with neurofibromatosis type 1 using measures of visual and sustained auditory attention, divided attention, selective attention, and response inhibition. Consistent with previous reports, we confirmed the presence of deficits in sustained visual and auditory attention in children with neurofibromatosis type 1 but also identified deficits in divided attention and response inhibition. Based on the high frequency and wide spectrum of attention system impairments in this at-risk population, we advocate screening children with neurofibromatosis type 1 for attention problems and providing appropriate interventions that address all aspects of their executive functioning. [ABSTRACT FROM AUTHOR]

It is well documented that children with neurofibromatosis type 1 are at high risk for a variety of cognitive and learning deficits. The current study investigated the use of a developmental screening tool, the Parents’ Evaluation of Developmental Status: Developmental Milestones, as an accurate, reliable, and efficient indicator of developmental delays. Sixty-eight percent of children with neurofibromatosis type 1 were found to have a developmental delay in at least 1 of the 8 areas tested by the Parents’ Evaluation of Developmental Status: Developmental Milestones. Significant developmental abnormalities were found in the areas of fine motor (35%), gross motor (52%), and math/premath (31%). A positive association was found between the presence of a previously diagnosed optic glioma and math/premath delays (χ2 = 0.0022) and between male sex and fine motor delays (χ2 = 0.0325). The Parents’ Evaluation of Developmental Status: Developmental Milestones assessment demonstrates the high presence of developmental delays in children with neurofibromatosis type 1 and the need for aggressive and early screening. [ABSTRACT FROM PUBLISHER]

Cowden syndrome is an autosomal dominant inherited cancer syndrome characterized by multiple hamartomas which may develop in any organ. Mucocutaneous papillomas and trichilemmomas are hallmarks of the syndrome. Affected individuals are at high risk of developing both benign and malignant disease of the thyroid and breast. Epithelial thyroid carcinoma occurs in 3–10% of affected individuals while women have a 25–50% lifetime risk of developing adenocarcinoma of the breast. Because of the cancer risk, it is imperative that health care providers recognize Cowden syndrome. The susceptibility gene has been localized to 10q22-23 and preliminary studies demonstrate no genetic heterogeneity. [ABSTRACT FROM AUTHOR]

The neurofibromatoses are a group of three heterogeneous disorders that include neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. NF1 is the most common of these three conditions, and represents one of the most frequently diagnosed cancer predisposition disorders involving the nervous system. While NF1 primarily affects the central and peripheral nervous system, multisystem involvement is the rule, with dermatologic, cardiovascular, gastrointestinal, and orthopedic affectation often reported. Importantly, NF1 is a disorder of heterogeneity, such that affected individuals can be variably affected, even within the same family. This heterogeneity also presents significant challenges to the actualization of effective treatments. However, recent studies aimed at understanding the role of the NF1 protein (neurofibromin) as a tumor suppressor have revealed that this profound level of clinical heterogeneity may reflect tissue and region-specific effects, sexually dimorphic influences, and the contribution of germline genetics and genomics. With the availability of accurate preclinical Nf1 small-animal models, human induced pluripotent stem cells, and an efficient clinical trials consortium, we are now uniquely positioned to identify and efficiently evaluate promising therapies for NF1-related medical problems., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The primary neurologic involvement in both von Hippel-Lindau (VHL) disease and Sturge-Weber syndrome (SWS) is vascular tumor/vascular malformation, but molecular pathogenesis, long-term symptom evolution, and treatment are quite different. VHL is caused by dominant inherited or de novo germline mutations, while SWS is caused by somatic mosaicism. A diagnosis of VHL carries substantial cancer risk, while the clinical issues in SWS are primarily related to the consequences of the intracranial vascular abnormalities., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Molecular epidemiology is the study of genetic and environmental risk for disease, with much effort centered on cancer. Childhood leukemia occurs in nearly a third of all patients newly diagnosed with pediatric cancer. only a small percentage of these new cases of childhood leukemia are associated with high penetrant hereditary cancer syndromes. Childhood leukemia, especially acute lymphoblastic leukemia, has been associated with a dysregulated immune system due to delayed infectious exposure at a young age. Identical twins with childhood leukemia suggest that acute lymphoblastic leukemia begins in utero and that the concordant presentation is due to a shared preleukemia subclone via placental transfer. Investigation of single nucleotide polymorphisms within candidate genes find that leukemia risk may be attributed to population-based polymorphisms affecting folate metabolism, xenobiotic metabolism, DNA repair, immunity, and B-cell development. More recently, genome-wide association studies for leukemia risk has led investigators to genes associated with B-cell development. When describing leukemia predisposition due to hereditary cancer syndromes, the following 6 categories become apparent on the basis of biology and clinical presentation: (1) genetic instability/DNA repair syndromes, (2) cell cycle/differentiation syndromes, (3) bone marrow failure syndromes, (4) telomere maintenance syndromes, (5) immunodeficiency syndromes, and (6) transcription factor syndromes and pure familial leukemia. understanding the molecular epidemiology of childhood leukemia can affect the treatment and tumor surveillance strategies for these high risk patients and their family members., (Copyright © 2016 American Federation for Medical Research.)