Lymphocytes subpopulation in normal family members of patients with alpha-chain disease.

Normal family members of eight diagnosed patients suffering from alpha-chain disease had been investigated by immunoelectrophoresis for abnormal alpha-chain protein in their serum. The pattern was demonstrated in four families only, of different members, but all are of the first-degree relationship. The aim of the study was to determine any possible hereditary defect of the immune system in such patients, as compared to the immune system of the normal members of the family who had abnormal protein in their serum. It was found that in both patients and normal members, the proportion of circulating B-lymphocytes was much higher than normal, whereas that of T-lymphocytes was lower than normal. Neither could be sensitized to DNCB, and their skin tests to tuberculin were negative. From all these findings, it was concluded that the disease was a B-cell disease of IgA type transmitted by a hereditary factor associated with a low level of cellular immunity. Further studies are required to support this hypothesis.     

Hypercoagulable states

The hypercoagulable state has been defined as the potential to develop thrombosis in association with hereditary and noninherited genetic mutations and acquired disorders. It is a condition that places an individual at risk for, but does not in itself inevitably lead to, thrombosis. The focus of this article is understanding mechanisms in the hypercoagulable state that enhance and maintain the production of thrombin in circulating blood while preventing its progression to thrombosis. These mechanisms include reactions that produce thrombin from prothrombin, feedback loop mechanisms that affect the rate of thrombin production from prothrombin and the inactivation of thrombin in blood. The fibrinolytic system is involved in clot lysis but not in thrombin production and inactivation.     

Knowledge, attitudes, and clinical experience of physicians regarding preimplantation genetic diagnosis for hereditary cancer predisposition syndromes

Approximately 5–10% of cancers are caused by an inherited predisposition. Individuals affected by hereditary cancer are often concerned about transmitting a predisposition to cancer to their children. Preimplantation genetic diagnosis (PGD) is a technology that allows embryos without a deleterious mutation associated with a hereditary cancer syndrome to be identified and implanted. The aim of this study is to assess the knowledge, attitudes, and clinical experience of physicians regarding PGD for hereditary cancer predisposition syndromes. Hereditary Breast and Ovarian Cancer (HBOC) and Familial Adenomatous Polyposis (FAP) are two hereditary cancer syndromes highlighted in this present study. A survey assessing physicians’ attitudes, knowledge, and clinical practice was completed by a total of 373 gynecologic oncologists (GYN ONCs) and obstetrics and gynecologists (OB/GYNs). Physicians had a limited knowledge of PGD for hereditary cancer; however, physicians reported PGD was an appropriate option for patients with either HBOC or FAP. Although GYN ONCs were more likely to care for patients with hereditary cancer (P < 0.001), they were less likely than OB/GYNs to refer their patients to a PGD specialist (P = 0.004). While 80% of GYN ONCs and 91% of OB/GYNs would refer patients to a PGD specialist, clinical experience indicates that only 29% actually referred their patients. Since 68% of physicians had incorrect or limited knowledge of PGD for hereditary cancer, there is a need for additional education.     

Antithrombin III concentrates.

The general characteristics of antithrombin III (AT III) concentrates available in the United States are described in this article. The effectiveness of AT III concentrates in the prevention and treatment of thrombotic episodes in patients with hereditary AT III deficiency are summarized, and the use of this product in various conditions with acquired AT III deficiency are reported.     

Cancer family history characterization in an unselected cohort of 121 patients with uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The extent of the contribution of familial/hereditary predisposition to the development of uveal melanoma is largely unknown. Thus we sought to ascertain the frequency of cancers in patients with UM and their family members to identify the prevalence of hereditary/familial predisposition to cancer in these patients. An unselected series of 121 patients with UM seen in a university-based tertiary referral program were consented to the study. Cancer histories (site and age of diagnosis) were obtained for all first- and second-degree relatives. Patients/families were classified as being potentially at high risk for hereditary predisposition if they met any of the following criteria: (1) Diagnosis of UM at age 30 or under, (2) Two or more cases of UM in the family, (3) UM plus at least one other primary cancer in the same patient (excluding non-melanoma skin and cervix cancers due to their strong environmental etiological link). (4) Family history meeting high risk criteria for a known hereditary cancer predisposition syndrome as defined by Hampel et al. (J Med Genet 41(2): 81–91, 2004). One patient had a family history of UM (0.8%). Ten patients (8.3%) had a personal and/or family history consistent with predisposition to a known hereditary cancer syndrome including six with possible hereditary breast, two with hereditary colon and two with hereditary melanomas. Twenty three patients (19%) had a personal history of a second cancer after exclusion of non-melanoma skin and cervical cancers. The frequency of cutaneous melanomas was significantly higher in UM patients than the general population (RR: 2.97, 95% CI: 1.00–6.94). Patients with a family history suggestive of a high risk predisposition to a known cancer syndrome had a significantly higher risk for having a second cancer than the remaining UM patients (P = 0.02). Our results indicate that the frequency of UM patients with high risk for a hereditary cancer predisposition is much higher than earlier estimates (0.6%) and that it could be as high as 11.6%. Our results suggest that cancer phenotypes in these patients are diverse and include cancers other than UM. Thus, alerting ophthalmologists to the need for expanding their cancer family history intake to include other cancers is warranted. It also suggests that patients with a hereditary predisposition to UM have a higher risk for the development of other cancers and that characterization of the germline genetic alterations in these patients is highly warranted.     

Acquired platelet function defects.

Platelet dysfunctions, especially acquired forms, are common causes of hemorrhage, especially when associated with trauma or surgery. Although the hereditary platelet function defects are generally quite rare, hereditary storage-pool disease is common enough to be suspected in an individual, usually a child, with characteristic historical and clinical findings. The acquired platelet function defects, especially those resulting from drugs, are very common and should promptly be suspected in patients developing easy and spontaneous bruising, mild to moderate mucosal membrane hemorrhage, or unexplained bleeding associated with trauma or surgery. The template bleeding time is generally useful as a screening test of platelet function, but a normal template bleeding time, in the face of a suggestive history, suggestive clinical findings, or in the patient frankly bleeding, is not reliable, and platelet aggregation or lumi-aggregation should be done in appropriate clinical situations. Also, prolongation of the template bleeding time is an unreliable predictor of clinical bleeding propensity. The mainstay of therapy for essentially all these defects, if bleeding is significant, is the liberal infusion of appropriate numbers of platelet concentrates. The acquired platelet function defects should also be managed by attempts to treat or control the underlying disease, if possible, and offending drugs or potentially offending drugs should immediately be stopped.     

Familial chronic myeloproliferative disorders: the state of the art

Familial chronic myeloproliferative disorders are defined when in the same pedigree at least two relatives have a chronic myeloproliferative disorder (CMD) as polycythemia vera (PV), essential thrombocythemia (ET) or primary myelofibrosis (PMF). This condition should be distinguished from inherited disorders with Mendelian transmission and single haematopoietic lineage proliferation, named hereditary erythrocytosis and thrombocytosis. The recently discovered mutations in patients with CMD (V617F and exon 12 of JAK2 gene, MPL gene), and those identified in hereditary erythrocytosis and in hereditary thrombocytosis have improved our ability to discriminate these conditions. In familial CMD, the JAK2 mutations are acquired and occur as secondary genetic events. As both mutations of the JAK2 gene have been reported in the same pedigree, a genetic predisposition to the acquisition of the JAK2 mutations is supposed to be inherited. The prevalence of familial cases within CMD is at least 7.6%. The inheritance pattern of familial CMD is consistent with an autosomal dominant trait with decreased penetrance. The clinical presentation at diagnosis of patients with familial CMD does not differ from that of patients with sporadic CMD. In addition, patients with familial CMD develop the same type of complications (thrombosis and haemorrhage) and disease evolution (post-PV myelofibrosis, post-ET myelofibrosis and leukaemia) observed in patients with sporadic CMD. The 10-year survival is 83% for patients with familial PV, 100% for those with familial ET, and 30% for those with familial PMF. The aim of this review is to focus the state of the art of familial CMD and to offer an overview of inherited conditions causing erythrocytosis and thrombocytosis.     

Pheochromocytoma: the expanding genetic differential diagnosis

Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.     

Strategies for clinical implementation of screening for hereditary cancer syndromes

Hereditary cancer syndromes generally account for 5%–10% of malignancies. While these syndromes are rare, affected patients carry significantly elevated risks of developing cancer, as do their at-risk relatives. Identification of these patients is critical to ensure timely and appropriate genetic testing relevant to cancer patients and their relatives. Several guidelines and tools are available to assist clinicians. Patients suspected to have hereditary cancer syndromes should be offered genetic testing in the setting of genetic counseling by a qualified genetics professional. Germline testing ranges from testing for a known specific familial mutation to testing of a broad differential diagnosis using a pan-cancer multi-gene panel. Taking a family history, referring specific types of tumors with higher likelihood of heredity, implementing universal screening protocols such as microsatellite instability/immunohistochemistry (MSI/IHC) for specific tumors, and referring patients with somatic tumor testing that have potentially germline consequences are all important components to the identification of hereditary cancer syndromes in the oncology clinic.     

Managing systemic light-chain amyloidosis

Amyloidosis is a rare disease in which a specific protein is deposited as aggregated interstitial fibrils that can compromise organ function and lead to death. Immunoglobulin (Ig) light-chain amyloidosis (AL), caused by the monoclonal gammopathy of a plasma cell dyscrasia, is the most common type. A hereditary type is also caused by mutant transthyretin and other proteins. Rarely, a patient with amyloid has both a monoclonal gammopathy and a hereditary protein. In AL, circulating monoclonal Ig light chains can be measured with the free light-chain (FLC) assay and provide a target for therapy to eliminate the underlying plasma cell dyscrasia while supporting the patient's organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor FLC is eliminated. For patients with limited organ involvement, intravenous melphalan in doses from 100 to 200 mg/m2 with autologous stem cell support (SCT) is an effective approach and, when followed at 3 months post-SCT with adjuvant thalidomide and dexamethasone for persistent plasma cell disease, has a 1-year hematologic response rate of 77%. Monthly oral melphalan and dexamethasone for 1 year can also be effective therapy for patients too sick for SCT (67% response rate). Hematologic complete responses are usually durable and result in long-term survival and a variable degree of organ recovery. For patients with advanced cardiac involvement, the prognosis remains guarded even with treatment. Drugs effective in multiple myeloma are usually active in AL, depending on side effects. New agents such as bortezomib and lenalidomide have shown promising activity, and novel antibody-based approaches for imaging amyloid and accelerating removal of deposits are being actively investigated.     

Exhausted platelets in patients with malignant solid tumors without evidence of active consumption coagulopathy

Twenty-four patients with various types of tumors and without evidence of consumption coagulopathy (normal routine coagulation tests) were investigated for intraplatelet ATP, ADP, serotonin, beta-thromboglobulin and platelet factor 4; the percentage of light circulating platelets was also determined. Evidence for an acquired storage pool defect was found in seven patients (29%) without any correlation with the clinical status, the presence of metastases, platelet count or fibrinogen level. These results show that exhausted platelets are commonly encountered in cancerous patients even in the absence of consumption coagulopathy. The precise mechanism of this abnormality remains to be established.     

The importance of paternal family history in hereditary breast cancer is underappreciated by health care professionals

OBJECTIVES: Cancer genetics clinics have been established in many major oncology centers worldwide in recent years. For such specialized clinics to fulfill their function, primary care physicians need to identify high-risk patients for referral. METHODS: We conducted a survey to evaluate the level of awareness of breast cancer risk factors and hereditary breast cancer among health care providers and patients. RESULTS: 284 health care professionals, 221 medical students, 104 breast cancer patients and 177 cancer-free women participated in the study. Less than half of the patients with breast cancer were aware of their risk for another breast cancer or of the increased breast cancer risk of their sisters and daughters. Less than one quarter of the health care professionals and medical students knew the importance of paternal family history in the evaluation for hereditary breast cancer. Only about half of the health care professionals and medical students and less than one third of the breast cancer patients and cancer-free women knew about genetic testing and prophylactic mastectomy as options for women at risk for hereditary breast cancer. CONCLUSIONS: Health care providers and medical students lack basic genetic knowledge and are not aware of emerging diagnostic and preventive options for hereditary breast cancer. Inclusion of cancer genetics in the continuing medical education of health care providers is important to promote such awareness.     

PGT在遗传性肿瘤生殖干预中的应用进展

遗传性肿瘤本质上是遗传物质缺陷导致的疾病,大多数呈现出孟德尔常染色体显性遗传规律,不仅危害患者的健康,而且对后代构成严重威胁。遗传性肿瘤胚胎植入前遗传学检测（preimplantation genetic testing,PGT）是利用外受精-胚胎移植（in vitro fertilization and embryo transfer,IVF-ET）和遗传学检测技术,对卵母细胞的极体、第3天的胚胎或第5天的囊胚进行遗传性肿瘤致病基因的检测,选择无遗传性肿瘤易感基因致病性变异的胚胎移植到子宫中,从而阻断遗传性肿瘤的子代传递并降低后代患病风险。本文简要介绍目前常见的遗传性肿瘤及其特征,总结PGT技术在家族性腺瘤性息肉病、遗传性乳腺癌/卵巢癌综合征等常见遗传性肿瘤及罕见遗传性肿瘤生殖干预中的应用,探讨遗传性肿瘤PGT技术的发展和伦理问题,并对其未来发展方向进行展望。     

Molecular genetic tools shape a roadmap towards a more accurate prognostic prediction and personalized management of cancer

The continuous flow of molecular genetic information has cautiously started integrating into clinical practice changing the future landscape of the clinical management of cancer. Germline mutation analysis for individuals at familial risk and testing result-based surgical or nonsurgical preventive intervention can protect from hereditary breast-ovarian, colorectal and stomach cancer and reduce mortality. Research is focusing now on the development of effective chemoprevention to replace prophylactic surgery for improving quality of life and to provide novel targeted therapies for hereditary cancer patients. The TNM staging system and conventional clinicopathologic factors have led clinical decisions on adjuvant therapy for decades improving survival in patients with early-stage tumors. However, current staging methods and therapeutic decisions remain suboptimal. Patients with early-stage cancer who are at low risk of recurrence could be spared the toxicity of systemic treatment if clearly distinguished, while others at high risk of distant recurrence could get maximal benefit if therapy matched the molecular genetic profile of either the host or the tumor. With the establishment of validated molecular analysis techniques it is believed that clinical biomarkers will gradually overtake TNM by their capacity to form more accurate prognostic systems and delineate better predictors of response to specific therapies. Areas of cancer research such as germ-cell mutation analysis, tumor gene-signature identification, gene expression profile linked targeted therapy, cancer stem cells, circulating cancer cells and single-nucleotide polymorphism keep on producing promising data which is believed to refine future preventive and early intervention strategies on an individual basis. Today these gene-based strategies are in a transition phase prior to full implementation into clinical practice. At present they wait for the results of large-scale prospective validation studies which compare molecular against "classic" markers. It is anticipated that molecular genetic biomarkers when implemented in clinical practice will considerably improve both biologically guided therapeutic decisions and clinical outcomes.     

Familial cancer database: a clinical aide-mémoire

Cancer is associated with a wide range of hereditary disorders. Recognizing these disorders in cancer patients may be of great importance for the medical management of both patients and their relatives. Conversely, recognizing the fact that cancer may develop in patients already diagnosed with a particular hereditary disorder may be important for the same reason. We have developed a stand-alone interactive computer program, Familial Cancer Database (FaCD), to assist the clinician in making a genetic differential diagnosis in cancer patients as well as in becoming aware of the tumour spectrum associated with a particular hereditary disorder. The program tries to match tumour and non-tumour features observed in patients and their families with any of the more than 300 disorders presently contained in its database and provides a clinical synopsis with literature references for each of these disorders. FaCD is offered free of charge in support of the Familial Cancer and Prevention project of the UICC Cancer Epidemiology and Prevention program. The software is primarily aimed at health care professionals with at least a basic knowledge of clinical cancer genetics, and can be downloaded from the internet at http://facd.uicc.org.     

遗传性非息肉病性大肠癌11个家系32例的临床特点与诊治

目的：分析遗传性非息肉病性大肠癌的临床特点及诊治经验。方法：分析11个家系32例遗传性非息肉病性大肠癌的诊断、治疗、随访结果，分别记录肿瘤发病部位、病理结果等一般情况。结果：11个家系中共有恶性肿瘤43例61个肿瘤，其中大肠癌32例39个肿瘤。32例中至今共发生异时多原发恶性肿瘤12例，占37．5％，其中异时多原发大肠癌5例，占15．6％。通过先证者对其本人及一级亲属进行随诊检查共发现各类恶性肿瘤28个，其中20个(67．7％)为无明显临床症状者。结论：本病是一种常染色体显性遗传病，本病具有发病年龄早，好发于近侧结肠，易患异时或同时多原发癌及大肠外恶性肿瘤。在诊治中要作详细病史调查，除对先证者进行治疗和随访外．对其亲属的宣教和随访等工作亦十分重要。     

Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines

Hereditary cancer predisposition syndromes comprise approximately 10% of diagnosed cancers; however, familial forms are believed to account for up to 30% of some cancers. In Hispanics, the most commonly diagnosed hereditary cancers include colorectal cancer syndromes such as, Lynch Syndrome, Familial Adenomatous Polyposis, and hereditary breast and ovarian cancer syndromes. Although the incidence of hereditary cancers is low, patients diagnosed with hereditary cancer syndromes are at high-risk for developing secondary cancers. Furthermore, the productivity loss that occurs after cancer diagnosis in these high-risk patients has a negative socio-economic impact. This review summarizes the genetic basis, phenotype characteristics, and the National Comprehensive Cancer Network’s screening, testing, and surveillance guidelines for the leading hereditary cancer syndromes. The aim of this review is to promote a better understanding of cancer genetics and genetic testing in Hispanic patients.     

Short report: Monitoring ESR1 mutations by circulating tumor DNA in aromatase inhibitor resistant metastatic breast cancer

Acquired estrogen receptor gene (ESR1) mutations have been recently reported as a marker of resistance to aromatase inhibitors in hormone receptor positive metastatic breast cancer. We retrospectively considered seven patients treated for metastatic breast cancer with available samples from the primary tumor before any treatment, cryopreserved metastasis removed during progression and concomitant plasmas. All these seven patients were in disease progression after previous exposure to aromatase inhibitors for at least 6 months, and were assessed for ESR1 mutations detection in tumor and circulating DNA. For these patients, Sanger sequencing identified four metastases with clear ESR1 mutation and one possible, whereas digital PCR identified six mutated metastases. Then, under blind conditions and using digital PCR, corresponding circulating ESR1 mutations were successfully detected in four of these six metastatic breast cancer patients. Moreover, in two patients with serial blood samples following treatments exposure, the monitoring of circulating ESR1 mutations clearly predicted disease evolution. In the context of high interest for ESR1 mutations, our results highlight that these acquired recurrent mutations may be tracked in circulating tumor DNA and may be of clinical relevance for metastatic breast cancer patient monitoring.     

Cancer mortality in long-term survivors of retinoblastoma

This study examined long-term cause-specific mortality among 998 Dutch retinoblastoma survivors, diagnosed from 1862 to 2005, according to follow-up time, treatment and heredity. After a median follow-up of 30.8 years, only cause-specific mortality for second malignancies among hereditary retinoblastoma survivors was statistically significantly increased with 12.8-fold. Risk of death from second malignancies among non-hereditary survivors was not increased. Mortality rates of second malignancy among hereditary patients were non-significantly elevated with 1.6-fold for treated with radiotherapy, compared to those treated otherwise. Standardised mortality ratios (SMRs) for second malignancy among hereditary patients increased during the first three decades after retinoblastoma diagnosis. Whereas these risks decreased after three decades, the absolute excess risk (AER) increased significantly, up to 23.2 excess cases per 1000 patients/year after five decades of follow-up. Fifty years after retinoblastoma diagnosis the cumulative mortality from any second malignancy was 17.3% for hereditary patients. Very long-term follow-up of retinoblastoma patients revealed an emerging excess risk of mortality in hereditary retinoblastoma survivors. This implies that lifelong follow-up is needed, whereas at the same time, patients and their physicians must be alerted to the increased second malignancy risks.     

Genetic testing by cancer site: urinary tract

ABSTRACT: The roles of renal cell carcinoma (RCC) and urothelial cancers of the upper urinary tract are often overlooked as indicators for genetic risk assessment. The key features of 5 hereditary cancer susceptibility conditions involving an increased risk for RCC are discussed. von Hippel-Lindau disease, hereditary papillary RCC, and hereditary leiomyomatosis and RCC each predispose to a specific histological type of RCC, whereas Birt-Hogg-Dubé and hereditary paraganglioma/pheochromocytoma entail a variety of histologic findings. Familiarity with the rare or uncommon clinical features associated with these conditions, such as cutaneous neoplasms, paraganglioma/pheochromocytoma, and recurrent spontaneous pneumothoraces, aids in identifying patients with an underlying RCC susceptibility. A path to identifying syndromic cases lies in thorough investigation of the patient's medical history, their family history, and the histological type of RCC reported in the family. A guide to genetic predisposition testing for RCC is proposed. Upper urinary tract cancers in Lynch syndrome are also discussed.