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1.
Fam Cancer ; 17(2): 247-253, 2018 04.
Article in English | MEDLINE | ID: mdl-28710566

ABSTRACT

Gastrointestinal stromal tumors (GISTs) occur mostly sporadically. GISTs associated with a familial syndrome are very rare and are mostly wild type for KIT and platelet-derived growth factor alpha (PDGFRA). To date 35 kindreds and 8 individuals have been described with GISTs associated with germline KIT mutations. This is the third family described with a germline p.Trp557Arg mutation in exon 11 of the KIT gene. The effect of imatinib in patients harboring a germline KIT mutation has been rarely described. Moreover, in some studies imatinib treatment was withheld considering the lack of evidence for efficacy of this treatment in GIST patients harboring a germline KIT mutation. This paper describes a 52-year old patient with a de novo germline p.Trp557Arg mutation with multiple GISTs throughout the gastrointestinal tract and cutaneous hyperpigmentation. Imatinib treatment showed long-term regression of the GISTs and evident pathological response was seen after resection. Remarkably, the hyperpigmentation of the skin also diminished during imatinib treatment. Genetic screening of the family revealed the same mutation in two daughters, both with similar cutaneous hyperpigmentation. One daughter, aged 23, was diagnosed with multiple small intestine GISTs, which were resected. She was treated with adjuvant imatinib which prompted rapid regression of the cutaneous hyperpigmentation. Imatinib treatment in GIST patients harboring a germline KIT mutation shows favorable and long-term responses in both the tumor and the phenotypical hyperpigmentation.


Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Stromal Tumors/drug therapy , Hyperpigmentation/drug therapy , Imatinib Mesylate/therapeutic use , Neoplastic Syndromes, Hereditary/drug therapy , Proto-Oncogene Proteins c-kit/genetics , Adult , Age of Onset , Antineoplastic Agents/pharmacology , Exons/genetics , Female , Gastrointestinal Stromal Tumors/diagnosis , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/pathology , Genetic Predisposition to Disease , Genetic Testing , Germ-Line Mutation , Humans , Hyperpigmentation/genetics , Imatinib Mesylate/pharmacology , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/pathology , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Rectum/diagnostic imaging , Rectum/pathology , Skin/drug effects , Skin/pathology , Stomach/diagnostic imaging , Stomach/pathology , Tomography, X-Ray Computed , Treatment Outcome , Young Adult
2.
Gynecol Oncol ; 144(2): 305-311, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27939984

ABSTRACT

OBJECTIVE: Women exposed to diethylstilbestrol in utero (DES) have an increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, while their risk of non-CCA invasive cervical cancer is still unclear. METHODS: We studied the risk of pre-cancerous (CIN) lesions and non-CCA invasive cervical cancer in a prospective cohort of 12,182 women with self-reported DES exposure followed from 2000 till 2008. We took screening behavior carefully into account. Incidence was obtained through linkage with the Netherlands Nationwide Pathology database (PALGA). General population data were also derived from PALGA. RESULTS: The incidence of CIN1 was increased (Standardized Incidence Ratio (SIR)=2.8, 95% Confidence Interval (CI)=2.3 to 3.4), but no increased risk was observed for CIN2+ (CIN2, CIN3 or invasive cancer) compared to the screened general population (SIR=1.1, 95% CI=0.95 to1.4). Women with DES-related malformations had increased risks of both CIN1 and CIN2+ (SIR=4.1, 95%CI=3.0 to 5.3 and SIR=1.5, 95%CI=1.1 to 2.0, respectively). For CIN2+, this risk increase was largely restricted to women with malformations who were more intensively screened. CONCLUSIONS: An increased risk of CIN1 among DES daughters was observed, especially in women with DES-related malformations, probably mainly due to screening. The risk of CIN2+ (including cancer) was not increased. However, among DES daughters with DES-related malformations a true small risk increase for non-CCA cervical cancer cannot be excluded.


Subject(s)
Abnormalities, Drug-Induced , Diethylstilbestrol/adverse effects , Prenatal Exposure Delayed Effects/chemically induced , Uterine Cervical Dysplasia/etiology , Uterine Cervical Neoplasms/etiology , Adult , Aged , Female , Humans , Middle Aged , Neoplasm Invasiveness , Papillomavirus Infections/complications , Pregnancy , Prospective Studies , Risk
3.
Br J Cancer ; 96(9): 1335-42, 2007 May 07.
Article in English | MEDLINE | ID: mdl-17426707

ABSTRACT

BRCA1/2 mutation carriers are offered gynaecological screening with the intention to reduce mortality by detecting ovarian cancer at an early stage. We examined compliance and efficacy of gynaecological screening in BRCA1/2 mutation carriers. In this multicentre, observational, follow-up study we examined medical record data of a consecutive series of 888 BRCA1/2 mutation carriers who started annual screening with transvaginal ultrasonography and serum CA125 between 1993 and 2005. The women were annually screened for 75% of their total period of follow-up. Compliance decreased with longer follow-up. Five of the 10 incident cancers were interval tumours, diagnosed in women with a normal screening result within 3-10 months before diagnosis. No difference in stage distribution between incident screen-detected and interval tumours was found. Eight of the 10 incident cancers were stage III/IV (80%). Cancers diagnosed in unscreened family members had a similar stage distribution (77% in stage III/IV). The observed number of cases detected during screening was not significantly higher than expected (Standardized Incidence Ratio (SIR): 1.5, 95% confidence interval: 0.7-2.8). For the subgroup that was fully compliant to annual screening, a similar SIR was found (1.6, 95% confidence interval: 0.5-3.6). Despite annual gynaecological screening, a high proportion of ovarian cancers in BRCA1/2 carriers are interval cancers and the large majority of all cancers are diagnosed in advanced stages. Therefore, it is unlikely that annual screening will reduce mortality from ovarian cancer in BRCA1/2 mutation carriers.


Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Mutation , Ovarian Neoplasms/genetics , Adult , CA-125 Antigen/analysis , Carrier State , Female , Follow-Up Studies , Humans , Mass Screening , Middle Aged , Neoplasm Staging , Observation/methods , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/pathology , Reproducibility of Results , Time Factors
4.
Blood ; 94(8): 2590-4, 1999 Oct 15.
Article in English | MEDLINE | ID: mdl-10515862

ABSTRACT

To analyze inherited antithrombin deficiency as a risk factor for venous thromboembolism in various conditions with regard to the presence or absence of additional genetic or acquired risk factors, we compared 48 antithrombin-deficient individuals with 44 nondeficient individuals of 14 selected families with inherited antithrombin deficiency. The incidence of venous thromboembolism for antithrombin deficient individuals was 20 times higher than among nondeficient individuals (1.1% v 0.05% per year). At the age of 50 years, greater than 50% of antithrombin-deficient individuals had experienced thrombosis compared with 5% of nondeficient individuals. Additional genetic risk factors, Factor V Leiden and PT20210A, were found in more than half of these selected families. The effect of exposure to 2 genetic defects was a 5-fold increased incidence (4.6% per year; 95% confidence interval [CI], 1.9% to 11.1%). Acquired risk factors were often present, determining the onset of thrombosis. The incidence among those with exposure to antithrombin deficiency and an acquired risk factor was increased 20-fold (20.3% per year; 95% CI, 12.0% to 34.3%). In conclusion, in these thrombophilia families, the genetic and environmental factors interact to bring about venous thrombosis. Inherited antithrombin deficiency proves to be a prominent risk factor for venous thromboembolism. The increased risks among those with exposure to acquired risk factors should be considered and adequate prophylactic anticoagulant therapy in high-risk situations seems indicated in selected families with inherited antithrombin deficiency.


Subject(s)
Antithrombins/deficiency , Thrombophilia/genetics , 3' Untranslated Regions/genetics , Abortion, Spontaneous/epidemiology , Abortion, Spontaneous/etiology , Adult , Age of Onset , Antithrombins/genetics , Comorbidity , Contraceptives, Oral, Hormonal/adverse effects , Factor V/analysis , Factor V Deficiency/epidemiology , Factor V Deficiency/genetics , Female , Humans , Incidence , Male , Middle Aged , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Pregnancy , Prothrombin/genetics , Puerperal Disorders/epidemiology , Puerperal Disorders/etiology , Risk , Risk Factors , Thrombophilia/epidemiology , Venous Thrombosis/epidemiology , Venous Thrombosis/etiology
5.
Semin Hematol ; 34(3): 188-204, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9241705

ABSTRACT

Antithrombin is the primary inhibitor of thrombin that also inhibits many of the other activated serine proteinases involved in blood coagulation. A hypercoagulable state occurs when a deficiency of antithrombin exists in plasma; the deficiency may be either inherited or acquired. This failure to regulate adequately the activity of coagulation proteinases can, with additional provocation, result in clot formation and in the clinical presentation of thromboembolic disease. The structure and function of antithrombin, nature and heterogeneity of the molecular defects in the antithrombin gene associated with inherited antithrombin deficiency, prevalence and the natural history of inherited antithrombin deficiency are all reviewed here.


Subject(s)
Antithrombin III Deficiency , Genetic Diseases, Inborn/blood , Antithrombin III/genetics , Antithrombin III/physiology , Blood Coagulation/genetics , Blood Coagulation/physiology , Genes/genetics , Genes/physiology , Genetic Diseases, Inborn/epidemiology , Humans , Point Mutation/genetics , Point Mutation/physiology
6.
Thromb Haemost ; 77(3): 452-5, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9065992

ABSTRACT

To assess the contribution of inherited antithrombin deficiency to mortality, we investigated the causes of death in 14 families with inherited antithrombin deficiency. Between 1830 and 1994, 86 of 266 family members who had a probability of 0.5 or more for heterozygosity died. The causes of death were obtained for 58 of 66 deaths occurring between 1940 and 1994. Standardized mortality ratios (SMR) were calculated using mortality rates from the general population adjusted for age, sex and calendar period. The overall SMR was 0.90 from 1830 to 1994 (95% C.I. 0.72-1.11). From 1940 until 1994 44 men and 22 women died (SMR = 1.09, 95% C.I. 0.84-1.39; SMR men = 1.20, 95% C.I. 0.87-1.61; SMR women = 0.92, 95% C.I. 0.58-1.39). No excess mortality compared to the general population was found for cancer (14 deaths) or circulatory diseases (28 deaths). A slightly increased mortality caused by respiratory diseases (7 deaths, SMR = 1.68, 95% C.I. 0.68-3.47) seemed due to pneumonia (4 deaths, SMR = 2.86, 95% C.I. 0.78-7.32). Venous thromboembolic complications were listed once in association with a risk situation, and one other death could be attributed to fatal pulmonary embolism. Cerebral hemorrhages were listed three times. It could not be verified whether these hemorrhages were related to anticoagulant therapy; the frequency was slightly higher than the expected population figure (SMR = 1.49, 95% C.I. 0.31-4.36). The mean age of death for all causes was 64 years; the two fatal thromboembolic episodes occurred at age 20 and 30 years. The data show that antithrombin deficiency is associated with a normal survival and a low risk of fatal thromboembolic events. The use of long-term anticoagulant treatment in asymptomatic individuals should be considered carefully in view of the greater risk of fatal bleeding associated with long-term anticoagulant prophylaxis.


Subject(s)
Antithrombin III Deficiency , Thromboembolism/mortality , Adult , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Cause of Death , Female , Humans , Male , Middle Aged , Poisson Distribution , Thromboembolism/genetics , Thromboembolism/prevention & control
7.
Thromb Haemost ; 75(3): 417-21, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8701400

ABSTRACT

We investigated the presence of the gene mutation of factor V, FV R506Q or factor V Leiden, responsible for activated protein C resistance, in DNA samples of 127 probands and 188 relatives from 128 families with antithrombin deficiency. The factor V mutation was identified in 18 families. Nine families were available to assess the mode of inheritance and the clinical relevance of combined defects. The factor V and antithrombin genes both map to chromosome 1. Segregation of the defects on opposite chromosomes was observed in three families. Co-segregation with both defects on the same chromosome was demonstrated in four families. In one family a de novo mutation of the antithrombin gene and in another a crossing-over event were the most likely explanations for the observed inheritance patterns. In six families with type I or II antithrombin deficiency (reactive site or pleiotropic effect), 11 of the 12 individuals with both antithrombin deficiency and the factor V mutation developed thrombosis. The median age of their first thrombotic episode was 16 years (range 0-19); this is low compared with a median age of onset of 26 years (range 20-49) in 15 of 30 carriers with only a defect in the antithrombin gene. One of five subjects with only factor V mutation experienced thrombosis at 40 years of age. In three families with type II heparin binding site deficiencies, two of six subjects with combined defects experienced thrombosis; one was homozygous for the heparin binding defect. Our results show that, when thrombosis occurs at a young age in antithrombin deficiency, the factor V mutation is a likely additional risk factor. Co-segregation of mutations in the antithrombin and factor V genes provides a molecular explanation for severe thrombosis in several generations. The findings support that combinations of genetic risk factors underly differences in thrombotic risk in families with thrombophilia.


Subject(s)
Antithrombin III/genetics , Factor V/genetics , Thrombosis/genetics , Adolescent , Adult , Antithrombin III Deficiency , Female , Genetic Testing , Humans , Male , Middle Aged , Mutation , Pedigree , Risk Factors
8.
Blood ; 84(12): 4209-13, 1994 Dec 15.
Article in English | MEDLINE | ID: mdl-7994035

ABSTRACT

We studied the molecular basis and genetic heterogeneity of hereditary antithrombin (III) deficiency in nine Dutch families. Polymerase chain reaction (PCR) amplification and direct sequencing of all antithrombin gene exons and flanking intronic regions identified mutations in eight families. Given the opportunity to correlate the molecular basis with survival, we addressed the relevance of molecular defects to mortality in inherited antithrombin deficiency. The defects included single nucleotide deletions (7671 del G, 7768-69 del G) and insertions (5501 ins A, 2463 G-->TC) that lead to frameshifts, a single base substitution [5381 C-->T (129Arg-->stop)] leading to a premature termination codon, and single base substitutions resulting in amino acid substitutions [2652 A-->C (63Tyr-->Ser), 13380 T-->C (421Ile-->Thr), and 13407 G-->T (430Cys-->Phe)]. All affected individuals were heterozygous for the defects. Previously we found in Dutch families that antithrombin deficiency did not lead to higher mortality compared with the general population. In accordance with these findings, we observed no excess mortality in the nine families [Observed:Expected, 52:52.6; standardised mortality ratio (SMR) 1.0, 95% confidence interval (CI), 0.7-1.3]. Our findings confirmed a considerable genetic heterogeneity underlying antithrombin deficiency. We therefore concluded that the lack of excess mortality in these families is not caused by a Dutch mild defect. We suggest that the longevity is not affected by molecular defects in the antithrombin gene and hypothesize that differences in mortality or natural history between families most likely result from other (genetic) risk factors.


Subject(s)
Antithrombin III Deficiency , Antithrombin III/genetics , Base Sequence , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/mortality , Heterozygote , Humans , Male , Molecular Sequence Data , Netherlands/epidemiology , Point Mutation , Sequence Deletion , Terminator Regions, Genetic
9.
Lancet ; 340(8826): 1048, 1992 Oct 24.
Article in English | MEDLINE | ID: mdl-1357446
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