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Vaishali I Parekh, Sita D Modali, James Welch, William F Simonds, Lee S Weinstein, Electron Kebebew, and Sunita K Agarwal

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Yulong Li, Jianhua Zhang, Poorni R Adikaram, James Welch, Bin Guan, Lee S Weinstein, Haobin Chen, and William F Simonds

Mutation of the CDC73 gene, which encodes parafibromin, has been linked with parathyroid cancer. However, no correlation between genotypes of germline CDC73 mutations and the risk of parathyroid cancer has been known. In this study, subjects with germline CDC73 mutations were identified from the participants of two clinical protocols at National Institutes of Health (Discovery Cohort) and from the literature (Validation Cohort). The relative risk of developing parathyroid cancer was analyzed as a function of CDC73 genotype, and the impact of representative mutations on structure of parafibromin was compared between genotype groups. A total of 419 subjects, 68 in Discovery Cohort and 351 in Validation Cohort, were included. In both cohorts, percentages of CDC73 germline mutations that predicted significant conformational disruption or loss of expression of parafibromin (referred as ‘high-impact mutations’) were significantly higher among the subjects with parathyroid cancers compared to all other subjects. The Kaplan–Meier analysis showed that high-impact mutations were associated with a 6.6-fold higher risk of parathyroid carcinoma compared to low-impact mutations, despite a similar risk of developing primary hyperparathyroidism between two groups. Disruption of the C-terminal domain (CTD) of parafibromin is directly involved in predisposition to parathyroid carcinoma, since only the mutations impacting this domain were associated with an increased risk of parathyroid carcinoma. Structural analysis revealed that a conserved surface structure in the CTD is universally disrupted by the mutations affecting this domain. In conclusion, high-impact germline CDC73 mutations were found to increase risk of parathyroid carcinoma by disrupting the CTD of parafibromin.

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Pamela Brock, Jennifer L Geurts, Paulien Van Galen, Erica Blouch, James Welch, Amy Kunz, Lauren Desrosiers, Jennifer Gauerke, and Samuel Hyde

The Genetic Counseling Working Group from the 16th International Workshop on Multiple Endocrine Neoplasia (MEN 2019) convened to discuss contemporary challenges and opportunities in the area of genetic counseling for individuals and families affected by hereditary endocrine neoplasia syndromes. As healthcare professionals with multidisciplinary training in human genetics, risk assessment, patient education, psychosocial counseling, and research methodology, genetic counselors bring a unique perspective to working toward addressing these challenges and identifying their subsequent opportunities. This Working Group focused on the following broad areas: (1) genetic counseling resources for endocrine neoplasias, (2) candidate gene discovery, (3) implications of increasingly sensitive and expansive genetic testing technologies for both the germline and the tumors, and (4) situating clinical diagnoses for hereditary endocrine neoplasia syndromes in the context of present-day knowledge.