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1.
Gut ; 69(3): 411-444, 2020 03.
Article in English | MEDLINE | ID: mdl-31780574

ABSTRACT

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.


Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapy , Population Surveillance , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/prevention & control , Adenomatous Polyposis Coli/therapy , Colonoscopy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/prevention & control , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/prevention & control , Colorectal Neoplasms, Hereditary Nonpolyposis/therapy , DNA Glycosylases/genetics , Family Health , Humans , Intestinal Polyposis/congenital , Intestinal Polyposis/genetics , Intestinal Polyposis/therapy , Ireland , Life Style , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/therapy , Peutz-Jeghers Syndrome/genetics , Peutz-Jeghers Syndrome/therapy , Referral and Consultation/standards , Risk Factors , United Kingdom
2.
J Med Genet ; 55(6): 384-394, 2018 06.
Article in English | MEDLINE | ID: mdl-29386252

ABSTRACT

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 in a large cohort of SDHB/SDHC/SDHD mutation carriers. METHODS: A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. RESULTS: Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). CONCLUSIONS: Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.


Subject(s)
Adrenal Gland Neoplasms/genetics , Membrane Proteins/genetics , Paraganglioma/genetics , Pheochromocytoma/genetics , Succinate Dehydrogenase/genetics , Adrenal Gland Neoplasms/pathology , Age Factors , Aged , Aged, 80 and over , Female , Genetic Association Studies , Genotype , Germ-Line Mutation/genetics , Heterozygote , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Mutation, Missense/genetics , Paraganglioma/pathology , Pheochromocytoma/pathology , Risk Factors , Sex Characteristics
3.
J Pediatr Hematol Oncol ; 38(2): 155-7, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26479990

ABSTRACT

We describe a child with advanced, metastatic, inoperable medullary carcinoma of thyroid associated with multiple endocrine neoplasia 2B and rearranged during transfection mutation with a positive response to vandetanib treatment. He responded well with a fall in calcitonin levels and a reduction in size of the thyroid malignancy, lymph nodes, and pulmonary metastases. He has been on vandetanib for 4 years with good clinical and biochemical response. Vandetanib has a role in the treatment of patients including children with inoperable locally advanced and metastatic medullary carcinoma of thyroid. More information is needed on its use in children and long-term outcome.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Neuroendocrine/drug therapy , Piperidines/therapeutic use , Quinazolines/therapeutic use , Thyroid Neoplasms/drug therapy , Carcinoma, Neuroendocrine/genetics , Child , Humans , Male , Multiple Endocrine Neoplasia Type 2a/complications , Thyroid Neoplasms/genetics
4.
Ann Clin Biochem ; 49(Pt 5): 486-90, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22914444

ABSTRACT

BACKGROUND: Catecholamine-producing neuroendocrine tumours are found in chromaffin cells of the adrenal medulla (phaeochromocytoma) or extra-adrenal paraganglia (paraganglioma), known collectively as PPGLs. In approximately a quarter or more of cases of PPGL, these rare tumours arise as a result of germline mutations of several tumour susceptibility genes. At the Crosshouse laboratory, urine tests include free metadrenalines (fMAs) (also known as free metanephrines) which demonstrate superior sensitivity over that obtained by urinary vanillyl mandelic acid, catecholamines or plasma catecholamines in the diagnosis of PPGL. This retrospective audit was to determine if urinary fMAs offered discrimination among the hereditary forms of PPGL. METHODS: Retrospective biochemical and genetic data were gathered from 1997 to 2011. The identified urine specimens were those obtained at the time of first diagnosis or recurrence of PPGL. Results of catecholamines and metabolites were standardized as multiples of their respective relevant upper reference limits (URLs). RESULTS: Results were available for 29 affected patients (15 females and 14 males), median age 26 (range 9-63) years, comprising three mutation groups: succinate dehydrogenase subunit B or D ([SDHB/D] 16 patients), multiple endocrine neoplasia type 2 ([MEN 2] 6 patients) and von Hippel-Lindau disease ([VHL] 7 patients). The parent catecholamines exhibited increased values for noradrenaline (NA) and/or adrenaline (AD) for 25/29 (86.2%) patients. Either or both free normetadrenaline (fNMA) and fMA were elevated in 29/29 (100%) patients. CONCLUSIONS: The ratio of the multiples of URL for fMA/fNMA displayed a clearer separation of MEN 2 patients from those with SDHB/D or VHL than did the equivalent AD/NA ratio.


Subject(s)
Adrenal Gland Neoplasms/urine , Catecholamines/urine , Metanephrine/urine , Paraganglioma/urine , Pheochromocytoma/urine , Adolescent , Adrenal Gland Neoplasms/genetics , Adult , Child , Clinical Chemistry Tests , Female , Humans , Male , Middle Aged , Paraganglioma/genetics , Pheochromocytoma/genetics , Recurrence , Retrospective Studies
5.
J Clin Endocrinol Metab ; 96(12): E2009-13, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21937622

ABSTRACT

CONTEXT: Pheochromocytoma/paraganglioma occurs almost exclusively after paternal transmission of succinate dehydrogenase D (SDHD) mutations. This parent-of-origin effect has not been fully explained but is accompanied by obligate loss of the maternal copy of chromosome 11. Loss of wild-type SDHD and an additional imprinted gene (hypothesized to be H19) appears necessary for tumor formation. Two previous reports suggested tumor formation after maternal transmission of SDHD mutation, but histological and molecular characterization was unavailable. OBJECTIVE: We report the first kindred in which histologically confirmed pheochromocytoma/paraganglioma occurred after maternal transmission of an SDHD mutation and investigate the molecular mechanism of tumor formation. DESIGN: The design of the investigation was the study of a three-generation family with SDHD c.242C>T (p.Pro81Leu) mutation. RESULTS: The index patient had a histologically confirmed pheochromocytoma and an identical SDHD germline mutation (p.Pro81Leu) to her mother (who had a glomus jugulare tumor) and paraganglioma tissue from her maternal grandfather. Tumor DNA from the index patient revealed loss of heterozygosity (LOH) at 11q23, causing loss of the wild-type paternal SDHD allele and LOH affecting maternal 11p15, including H19. These two regions of LOH were separated by a region exhibiting clearly retained heterozygosity, including SDHAF2, a recently reported paraganglioma susceptibility gene. CONCLUSIONS: Tumor formation can occur after maternal transmission of SDHD, a finding with important clinical implications for SDHD families. Tumor formation in SDHD mutation requires the loss of both the wild-type SDHD allele and maternal 11p15, leading to the predominant but now not exclusive pattern of disease inheritance after paternal SDHD transmission.


Subject(s)
Adrenal Gland Neoplasms/genetics , Germ-Line Mutation , Pheochromocytoma/genetics , Succinate Dehydrogenase/genetics , Alleles , Chromosomes, Human, Pair 11 , DNA Mutational Analysis , Female , Humans , Loss of Heterozygosity , Male , Pedigree
6.
Hum Mutat ; 31(1): 41-51, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19802898

ABSTRACT

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%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma.


Subject(s)
Adrenal Gland Neoplasms/genetics , Germ-Line Mutation , Paraganglioma/genetics , Pheochromocytoma/genetics , Succinate Dehydrogenase/genetics , Adolescent , Adrenal Gland Neoplasms/pathology , Adult , Aged , Child , Child, Preschool , DNA Mutational Analysis , Female , Genetic Predisposition to Disease , Genotype , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Paraganglioma/pathology , Phenotype , Pheochromocytoma/pathology , Young Adult
7.
Fam Cancer ; 7(4): 361-6, 2008.
Article in English | MEDLINE | ID: mdl-18560993

ABSTRACT

Published guidelines adopted in many countries recommend that women whose family history of breast cancer places them at a risk>or=1.7 times that of the age-matched general population, should be considered for inclusion in special surveillance programmes. However validation of risk assessment models has been called for as a matter of urgency. The databases of the four Scottish Familial Breast Cancer clinics and the Scottish Cancer Registry have been searched to identify breast cancers occurring among 1,125 women aged 40-56, with family histories placing them below the "moderate" level of genetic risk. The observed incidence over 6 years was compared with age-specific data for the Scottish population. Our findings confirm that when there are two affected relatives (one first degree) the relative risk (RR) exceeds 1.7 regardless of their ages at diagnosis. When only one (first degree) relative was affected at any age from 40 to 55, the RR does not reach 1.7 if that relative was a mother but exceeds it if the relative was a sister. The probable explanation is that sisters are more likely than mother/daughter pairs to share homozygosity for a risk allele. Surveillance programmes might therefore accommodate sisters of women affected before age 55. Evidence that "low penetrance" alleles contributing to breast cancer risk may be recessive should be taken into account in strategies for identifying them.


Subject(s)
Breast Neoplasms/genetics , Genetic Predisposition to Disease , Adult , Breast Neoplasms/epidemiology , Cohort Studies , Family Health , Female , Humans , Middle Aged , Risk Assessment , Siblings
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