Shirley V Hodgson

St. George's School · Department of Medical Genetics

Background: Around 95% of patients with clinical features diagnostic of Von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the VCB-CR complex which plays a key role in oxygen sensing and degradation of hypoxia inducible factors. To date, only variants in VHL has been...

Background Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype–phenotype correlations...

Background:Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations...

The primary aim of this, the seventeenth COMARE report, is to provide the Department of Health and the Scottish Government with a review of the incidence of childhood leukaemia and other cancers around the Sellafield and Dounreay nuclear installations, bringing the analyses up to date. In addition to the incidence of childhood cancers in the 0–14 y...

Background: The strongest known risk factor for endometrial cancer (EC) is obesity. To determine whether single nucleotide polymorphisms (SNPs) associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with EC risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and EC in 6,6...

Thyroid cancers are largely divided into medullary (MTC) and non-medullary (NMTC) cancers , depending on the cell type of origin. Familial non-medullary thyroid cancer (FNMTC) comprises about 5–15 % of NMTC and is a heterogeneous group of diseases, including both non-syndromic and syndromic forms. Non-syndromic FNMTC tends to manifest papillary thy...

No abstract is available for this article.

In the summer of 2014, at the height of the Israeli Defence Force’s ‘Operation Protective Edge’, The Lancet published ‘An open letter for the people in Gaza’ signed by Paola Manduca, Iain Chalmers, Derek Summerfield, Mads Gilbert and Swee Ang, on behalf of 24 signatories. The letter denounced what it called ‘the aggression of Gaza by Israel’ and co...

IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE:To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS:Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to car...

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variant...

The Committee on Medical Aspects of Radiation in the Environment (COMARE) was established in November 1985 in response to the final recommendation of the report of the Independent Advisory Group chaired by Sir Douglas Black (Black, 1984). The terms of reference for COMARE are: ‘to assess and advise government and the devolved authorities on the hea...

Squamous carcinomas of the head and neck (a grouping which includes tongue and mouth, nasopharynx, and larynx) are associated with cigarette smoking and alcohol ingestion (although the risk factors for different sites may differ). In addition, infection with human papillomavirus (HPV) is associated with cancers of the oropharynx (D’Souza et al. 200...

In general, sarcomas of bone, muscle, or connective tissue are rare, especially in children. Bone tumors comprise about 5 % of childhood cancers (3 % osteosarcomas and 2 % Ewing sarcoma), and their incidence overall is about 10 per million persons in the UK. The age-standardized rate of malignant bone tumors for white children (0–14 years of age) i...

Cancers of the kidney account for approximately 1.5 % of all cancers and cancer deaths (with an incidence of 5–8 per 100,000 population in the UK and commoner in males). Three main types of renal cancer are distinguished: (1) Wilms tumor, (2) renal cell carcinoma (RCC) (adenocarcinoma), and (3) medullary and transitional cell cancers of the renal p...

The incidence of primary epithelial cancer of the thyroid is 0.7 per 100,000 in males and 1.9 per 100,000 in females in the UK. Overall, the annual incidence of thyroid cancer is between 0.9 and 5.2 per 100,000 people, with a ratio of women to men of 2–3:1. Thyroid cancer is the most rapidly rising incident cancer in women and the second most rapid...

Breast cancer is the most common non-cutaneous cancer in women, accounting for 20 % of all new cases of cancer. The lifetime risk of breast cancer in the UK is one in nine females, with an annual incidence of <10 per 100,000 women aged <30 years, rising to 300 per 100,000 in women aged over 85 years. Similar, but slightly higher rates are seen in N...

Leukemia is responsible for approximately 2 % of all cancers, with an incidence of about 8 per 100,000 in the UK. Acute myeloid and lymphoblastic leukemia (AML and ALL) account for about 1 % of all cancers and 1.5 % of cancer deaths. The age incidence of leukemia shows two peaks, in childhood and in the elderly. Genetic factors are not considered t...

Tumors at this site occur with a frequency of about 1 per 100,000 population. They are commoner in Spanish, Inuit, Indian, and Cantonese Chinese populations, but do not appear to have a strong genetic basis. Familial occurrence of mixed salivary tumors has been reported infrequently (Klausner and Handler 1994), and it is difficult to know whether t...

This autosomal recessive disorder, with a birth incidence of about 1 in 300,000, is characterized by the development of cerebellar ataxia in the first decade, along with choreoathetosis, dysarthria, and abnormalities of ocular movements. Mental retardation is not usually a feature. The neurological features are progressive, leading to confinement t...

The Committee on Medical Aspects of Radiation in the Environment (COMARE) was established in November 1985 in response to the final recommendation of the report of the Independent Advisory Group chaired by Sir Douglas Black (Black, 1984). The terms of reference for COMARE are: ‘to assess and advise government and the devolved authorities on the hea...

Context: Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-α11 (GNA11) gain-of-function mutations, respectively, whereas CASR and GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor...

This is a comprehensive and up-to-date guide to the diagnosis, clinical features and management of inherited disorders conferring cancer susceptibility. This new edition is fully updated with much more molecular, screening and management information. It covers risk analysis and genetic counseling for individuals with a family history of cancer, and...

Changes in DNA methylation, whether hypo- or hyper-methylation, have been shown to be associated with progression of colorectal cancer. Methylation changes substantially in the progression from normal mucosa, to adenoma and to carcinoma. This phenomenon has not been studied extensively, and studies have been restricted to individual CpG islands rat...

Investigation of rare familial forms of renal cell carcinoma (RCC) has led to the identification of genes such as VHL and MET that are also implicated in the pathogenesis of sporadic RCC. In order to identify a novel candidate renal tumour suppressor gene, we characterised the breakpoints of a constitutional balanced translocation, t(5;19)(p15.3;q1...

Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data o...

Context: Pheochromocytomas and paragangliomas are notable for a high frequency of inherited cases, many of which present as apparently sporadic tumors. Objective: The objective of this study was to establish a comprehensive next generation sequencing (NGS)-based strategy for the diagnosis of patients with pheochromocytoma and paraganglioma by te...

Protocols for SLIT2 MSP, SLIT2 pyrosequencing, BRAF sequencing and 4p15 microsatellite PCR. (DOCX)

Serrated adenomas form a distinct subtype of colorectal pre-malignant lesions that may progress to malignancy along a different molecular pathway than the conventional adenoma-carcinoma pathway. Previous studies have hypothesised that BRAF mutation and promoter hypermethylation plays a role, but the evidence for this is not robust. We aimed to carr...

Accurate duplication of DNA prior to cell division is essential to suppress mutagenesis and tumour development. The high fidelity of eukaryotic DNA replication is due to a combination of accurate incorporation of nucleotides into the nascent DNA strand by DNA polymerases, the recognition and removal of mispaired nucleotides (proofreading) by the ex...

Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantia...

Lynch Syndrome, an autosomal dominantly inherited cancer predisposition syndrome is not typically associated with development of breast cancer. We present two cases of loss of mismatch protein expression in breast cancer cases in patients with Lynch Syndrome and discuss the literature surrounding the subject.

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-ad...

Repair of double strand DNA breaks (DSBs) is pivotal in maintaining normal cell division and disruption of this system has been shown to be a key factor in carcinogenesis. Loss of expression of the DSB repair proteins have previously been shown to be associated with poorer survival in colorectal cancer. We wished to ascertain the relationship of al...

Repair of double strand DNA breaks (DSBs) is pivotal in maintaining normal cell division and disruption of this system has been shown to be a key factor in carcinogenesis. Loss of expression of the DSB repair proteins have previously been shown to be associated with poorer survival in colorectal cancer. We wished to ascertain the relationship of al...

Research studies have reported that about a third of individuals with phaeochromocytoma/paraganglioma (PPGL) have an inherited predisposition, although the frequency of specific mutations can vary between populations. We evaluated VHL, SDHB and SDHD mutation testing in cohorts of patients with non-syndromic PPGL and head and neck paraganglioma (HNP...

Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptoma...

Patients with germline phosphatase and tensin homologue (PTEN) mutations develop hamartomatous lesions in several organs and are at increased risk of various malignancies. We assessed the lifetime risk of benign and malignant gastrointestinal lesions in patients with a proven PTEN mutation. Data on gender, mutation, dates of birth, last contact, an...

Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer. We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from...

Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators o...

Around one-third of the world's population already live in countries that suffer from moderate to high water stress. Continued population growth leads to increased water demand to meet basic needs as well as food production, and the effects of climate change suggest greater pressure still. It has been estimated that the demand for water will increa...

Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syn...

The Committee on Medical Aspects of Radiation in the Environment (COMARE) was established in November 1985 in response to the final recommendation of the report of the Independent Advisory Group chaired by Sir Douglas Black (Black, 1984).The terms of reference for COMARE are: ‘to assess and advise Government and the devolved authorities on the heal...

The MUTYH gene encodes a DNA glycosylase involved in base excision repair (BER). Biallelic pathogenic MUTYH variants have been associated with colorectal polyposis and cancer. The pathogenicity of a few variants is beyond doubt, including c.536A4G/p.Tyr179Cys and c.1187G4A/p.Gly396Asp (previously c.494A4G/p.Tyr165Cys and c.1145G4A/p.Gly382Asp).Howe...

Carney triad is a usually sporadic association of pulmonary chondroma, gastrointestinal stromal tumours, and paraganglioma. The majority of patients have two of these tumours, the gastric and pulmonary tumours being the most common combination. Carney Stratakis syndrome is an association of familial paraganglioma and gastric stromal sarcoma and it...

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%,...

The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.

The purpose of this report by the Committee on Medical Aspects of Radiation in the Environment (COMARE) is to provide advice to government on the health effects and risks from UV sunbeds, recommending actions that could be taken forward by all 4 UK health departments and other government departments with an interest in this issue.

Moderate and severe learning disabilities are defined as conditions in which intellectual capacity is compromised, with the likelihood that there will be no catch-up development.

Familial renal cell carcinoma (RCC) is genetically heterogeneous. The most common histopathologic subtype of sporadic and familial RCC is clear cell (cRCC) and von Hippel-Lindau (VHL) disease is the most common cause of inherited cRCC. Familial cRCC may also be associated with chromosome 3 translocations and has recently been described in patients...

DESIGN: A case of Nance‐Horan syndrome in a male is presented, with some features of the condition in his carrier mother and her mother. It is proposed that Nance‐Horan syndrome might be a contiguous gene syndrome mapping to chromosome Xp21.2–p22.3. SETTING: The proband had congenital cataract micro‐phthalmia and dental abnormalities including scre...

Before publication of the British Society of Gastroenterology and Association of Coloproctology of Great Britain and Ireland guidelines in 2002, screening for people with a family history of colorectal cancer was sporadic and largely dependant on unvalidated local guidelines. Since 1990 we have been screening patients with both high and moderate ri...

The concept of the adenoma-carcinoma sequence, as first espoused by Morson et al. whereby the development of colorectal cancer is dependent on a stepwise progression from adenomatous polyp to carcinoma is well documented. Initial studies of the genetics of inherited colorectal cancer susceptibility concentrated on the inherited colorectal cancer s...

Patents on genes often cover the gene sequence and the link between a disease and mutations in a gene, rather than a technology for the identification of mutations per se. Normally, patents are important for encouraging the development of new diagnostic tools and kits, but there is evidence that they can have severely deleterious effects on the del...

MYH associated polyposis is an autosomal recessive polyposis syndrome with a high risk of large bowel cancer, caused by mutations in the DNA repair gene MYH. Founder mutations have been described in different ethnic groups. Muir Torre Syndrome is the association of internal malignancies with sebaceous gland tumours; Lynch Syndrome/Hereditary Non Po...

This report by the Committee on Medical Aspects of Radiation in the Environment (COMARE) looks at the justification of these scanning procedures, including CT scans of the whole body and of key anatomical areas, the latter being designed to allay the concerns of asymptomatic individuals with regard to defined diseases. It has taken into considera...

There is conflicting evidence as to whether individuals who are heterozygous for germ-line BRCA1 or BRCA2 mutations have an altered phenotypic cellular response to irradiation. To investigate this, chromosome breakage and apoptotic response were measured after irradiation in peripheral blood lymphocytes from 26 BRCA1 and 18 BRCA2 mutation carriers...

Individuals who have been treated for breast cancer have been reported to have increased lymphocyte chromosomal sensitivity to ionizing radiation and a significantly lower apoptotic response to irradiation compared to controls. We set out to test these findings using a substantial number of cases sampled before treatment (which could alter the para...

This study assessed current practice and methods for improvement in the management of families with hereditary non-polyposis colorectal cancer (HNPCC). HNPCC families registered at five London Genetics Centres and a specialised Colorectal family cancer clinic (CFCC) were identified. Ascertainment of management and outcome details were obtained by s...

Activation of the hypoxia-inducible transcription factors HIF-1 and HIF-2 and a HIF-independent defect in developmental apoptosis have been implicated in the pathogenesis of pheochromocytoma (PCC) associated with VHL, SDHB, and SDHD mutations. Our objective was to compare protein (HIF-1alpha, EPAS1, SDHB, JunB, CCND1, CD34, CLU) and gene (VEGF, BNI...

Lionel Penrose (1898–1972) was a British geneticist who pioneered human genetics, and developed mathematical data analysis and sibling-pair analysis for use in genetic studies. Keywords: sib-pair analysis; learning difficulties; human genetics; intellectual impairment

The aim of this report by the Committee on Medical Aspects of Radiation in the Environment (COMARE) is to provide an overview of the geographical patterns of variation in the incidence of different types of childhood cancer, and the relation of these to certain socio-demographic factors, and to examine whether spatial or space–time clustering are p...

Two breast cancer susceptibility genes have been identified, BRCA1 and BRCA2, which when inherited in altered form, confer a substantially increased risk of breast and ovarian cancer. Genetic testing for mutations in the BRCA1 and BRCA2 genes is available to adult men and women at increased risk of carrying such a mutation based on their personal a...

BRCA1 exon deletions and duplications have been reported in a number of studies, and in order to design an effective mutation screening strategy in a diagnostic setting it is import to determine the frequency of this type of mutation in breast and ovarian cancer patients. We have designed and applied quantitative fluorescent PCR (QF-PCR) assays to...

A 72 years old lady was referred to endocrine clinic with raised serum calcium of 2.69mmol/l and PTH of 99.6 ng/l (3.0 - 48.0ng/l) detected during investigations for an abnormal skeletal survey. She was known to have osteoporosis from the age of 59 diagnosed on Dexa scan. Case notes revealed raised serum calcium of 2.52 - 2.60mmol/lsince year 2000....