The Journal of Clinical Endocrinology & Metabolism
Context Somatic EPAS1 variants account for 5% to 8% of all pheochromocytoma and paragangliomas (P... more Context Somatic EPAS1 variants account for 5% to 8% of all pheochromocytoma and paragangliomas (PPGL) but are detected in over 90% of PPGL in patients with congenital cyanotic heart disease, where hypoxemia may select for EPAS1 gain-of-function variants. Sickle cell disease (SCD) is an inherited hemoglobinopathy associated with chronic hypoxia and there are isolated reports of PPGL in patients with SCD, but a genetic link between the conditions has yet to be established. Objective To determine the phenotype and EPAS1 variant status of patients with PPGL and SCD. Methods Records of 128 patients with PPGL under follow-up at our center from January 2017 to December 2022 were screened for SCD diagnosis. For identified patients, clinical data and biological specimens were obtained, including tumor, adjacent non-tumor tissue and peripheral blood. Sanger sequencing of exons 9 and 12 of EPAS1, followed by amplicon next-generation sequencing of identified variants was performed on all sample...
BackgroundGermline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developi... more BackgroundGermline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms.MethodsPsychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks’ follow-up.ResultsWB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity...
Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subt... more Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P<5.0x10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate <0.05). Five loci showed associations (P<0.05) in opposite directions between luminal- and non-luminal subtypes. In-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between fi...
Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and ex... more 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 co...
The Journal of Clinical Endocrinology & Metabolism
Context Somatic EPAS1 variants account for 5% to 8% of all pheochromocytoma and paragangliomas (P... more Context Somatic EPAS1 variants account for 5% to 8% of all pheochromocytoma and paragangliomas (PPGL) but are detected in over 90% of PPGL in patients with congenital cyanotic heart disease, where hypoxemia may select for EPAS1 gain-of-function variants. Sickle cell disease (SCD) is an inherited hemoglobinopathy associated with chronic hypoxia and there are isolated reports of PPGL in patients with SCD, but a genetic link between the conditions has yet to be established. Objective To determine the phenotype and EPAS1 variant status of patients with PPGL and SCD. Methods Records of 128 patients with PPGL under follow-up at our center from January 2017 to December 2022 were screened for SCD diagnosis. For identified patients, clinical data and biological specimens were obtained, including tumor, adjacent non-tumor tissue and peripheral blood. Sanger sequencing of exons 9 and 12 of EPAS1, followed by amplicon next-generation sequencing of identified variants was performed on all sample...
BackgroundGermline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developi... more BackgroundGermline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms.MethodsPsychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks’ follow-up.ResultsWB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity...
Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subt... more Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P<5.0x10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate <0.05). Five loci showed associations (P<0.05) in opposite directions between luminal- and non-luminal subtypes. In-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between fi...
Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and ex... more 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 co...
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