Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp(TGC>TGG) mutation

MILOS IOANA N; FRANK-RAUE KARIN; WOHLLK NELSON; MAIA ANA LUIZA; PUSIOL EDUARDO; PATOCS ATTILA; ROBLEDO MERCEDES; BIARNES JOSEFINA; BARONTINI MARTA; LINKS THERA P; DE GROOT JAN WILLEM; DVORAKOVA SARKA; PECZKOWSKA MARIOLA; RYBICKI LISA A; SULLIVAN MAREN; RAUE FRIEDHELM; ZOSIN IOANA; ENG CHARIS; NEUMANN HARTMUT P H

Endocrine-Related Cancer

Society for Endocrinology

Lugar: Gran Bretaña; Año: 2008 vol. 15 p. 1035 - 1041

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics.However, precise data for distinctmutation-based risk profiles are not available.Here, wesurvey the clinical profile for one specific genotype as amodel, TGCto TGGin codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3–72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20–72 and distant metastases in 4 subjects aged 28–69. Forty-one subjects had pheochromocytoma detected at age 18–67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26–52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20%by age 30 and 67%by age 50, and forHPTpenetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics.However, precise data for distinctmutation-based risk profiles are not available.Here, wesurvey the clinical profile for one specific genotype as amodel, TGCto TGGin codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3–72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20–72 and distant metastases in 4 subjects aged 28–69. Forty-one subjects had pheochromocytoma detected at age 18–67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26–52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20%by age 30 and 67%by age 50, and forHPTpenetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3–72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20–72 and distant metastases in 4 subjects aged 28–69. Forty-one subjects had pheochromocytoma detected at age 18–67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26–52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20%by age 30 and 67%by age 50, and forHPTpenetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.