Ovarian sex cord-stromal tumors, pleuropulmonary blastoma and DICER1 mutations: A report from the International Pleuropulmonary Blastoma Registry
Kris Ann P. SchultzM. Cristina PachecoJiandong YangGretchen M. WilliamsYoav H. MessingerD. Ashley HillLouis P. DehnerJohn R. Priest
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Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1-2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype-phenotype correlations in VHL.
Von Hippel–Lindau disease
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Germline mosaicism
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Abstract Currently, there are at least a dozen recognized hereditary hematopoietic malignancies (HHMs), some of which phenocopy others. Among these, three HHMs driven by germline mutations in ANKRD26, ETV6 , or RUNX1 share a phenotype of thrombocytopenia, qualitative platelet defects, and an increased lifetime risk of hematopoietic malignancies (HMs). Prior work has demonstrated that RUNX1 germline mutation carriers experience an elevated lifetime risk (66%) for developing clonal hematopoiesis (CH) prior to age 50. Germline mutations in ANKRD26 or ETV6 phenocopy RUNX1 germline mutations, but no studies have focused on the risk of CH in individuals with germline mutations in ANKRD26 or ETV6 . To determine the prevalence of CH in individuals with germline mutations in ANKRD26 or ETV6 , we performed next generation sequencing on hematopoietic tissue from twelve individuals with either germline ANKRD26 or germline ETV6 mutations. Each patient had thrombocytopenia but had not developed HMs. Among the seven individuals with germline ANKRD26 mutations, one patient had a CH clone driven by a somatic SF3B1 mutation (p.Lys700Glu). This mutation increased from a variant allele frequency (VAF) of 9.4% at age 56 to 17.4% at age 60. None of the germline ETV6 mutation carriers had evidence of CH at the limits of detection of the NGS assay (5% VAF). Unlike individuals with germline mutations in RUNX1 , no individuals under the age of 50 with germline mutations in ANKRD26 or ETV6 had detectable CH. This work demonstrates that ANKRD26 germline mutation carriers, but not ETV6 mutation carriers, experience elevated risk for CH.
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Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1–2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype-phenotype correlations in VHL. © 1996 Wiley-Liss, Inc.
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Abstract The germline mutation rate has been extensively studied and has been found to vary greatly between species, but much less is known about the somatic mutation rate in multicellular organisms, which remains very difficult to determine. Here, we present data on somatic mutation rates in mice and humans, obtained by sequencing single cells and clones derived from primary fibroblasts, which allows us to make the first direct comparison with germline mutation rates in these two species. The results indicate that the somatic mutation rate is almost two orders of magnitude higher than the germline mutation rate and that both mutation rates are significantly higher in mice than in humans. Our findings demonstrate both the privileged status of germline genome integrity and species-specific differences in genome maintenance.
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Background Malignant Melanoma (MM) is familial in 5–7% of cases. Germline mutations of the CDKN2 and CDK4 genes are involved in the pathogenesis of hereditary MM, but the high frequency of familial clustering suggests other genes involved. MM seems to cluster with hereditary syndrome such as Hereditary Breast/Ovarian Cancer (HBOC). In this respect, some authors reported that carriers of BRCA 2 germline mutations have a significantly increased risk for MM (RR: 2.58). AIMS We investigate family history of MM patients to define the familial clustering for MM and history for other tumours. Methods We retrospectively analysed family history of 342 consecutive MM cases referred from 1994 to 2002 to the “Gruppo Melanoma”, Azienda Universitaria Policlinico, University “Federico II” of Naples. We divided the cases into four subsets: 1) multiple MM; 2) MM aggregated with other tumours in the proband; 3) MM with a family history of MM; and 4) MM with a family history of other tumours. We collected the pedigree, after informed consent, in all cases with a family history of MM or other tumours. Results Data analysis showed: multiple MM in 5/342 cases (1.46%); MM aggregated with other tumours in the proband in 10/342 cases (2.9%); MM with a family history of MM in 13/342 cases (3.8%) and MM with a family history of other tumours in 28/342 cases (8.2%). We propose pedigree construction to 41 subjects: we collected 23 pedigrees, 14 pedigree are ongoing, while 4 cases refused their consent. Conclusion Patient affected by Malignant Melanoma seems to be at increased risk to develop other tumours and healthy individuals belonging to families with a high clustering for malignant melanoma and other tumours could be at risk for cancers. Supported by MIUR-COFIN 2001.
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We present an infant with 2 simultaneous, but histologically distinct tumors with a novel germline p53 mutation. The child was found to have a paraspinal neuroblastoma, a concurrent adrenal cortical carcinoma, and an I162F p53 gene mutation. We review the associations of germline p53 mutations (or Li-Fraumeni syndrome) with both tumor types and the current research in similar germline p53 mutations. Finally, we discuss the multiple ways in which our patient is unique including the paucity of cases with simultaneous but histologically unrelated tumors and the fact that our patient is the first reported case of an I162F germline p53 mutation.
Li–Fraumeni syndrome
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Brief Summary: This study investigated the mutational background of somatic cells and rates of mutation in 29 distinct anatomical structures and compared these with the male germline from the same donor. The rate of mutation was lowest in spermatogonia.
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