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Cancer of the urologic system accounts for substantial morbidity and mortality in the United States each year. A subset of individuals with urologic malignancies has cancer due to alterations in a major predisposing gene. While several heritable renal cancer syndromes are well characterized, the hereditary nature and genetic basis of other urologic malignancies is not yet clarified. Nursing roles are increasingly affected by the rapid influx of genetic knowledge. Current advances in the genetic basis of genitourinary cancer and the implications of these advances for urologic nursing practice are addressed. [ABSTRACT FROM AUTHOR]

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant condition characterized by the development of cutaneous and uterine leiomyomas and risk for development of an aggressive form of papillary renal cell cancer. HLRCC is caused by germline inactivating pathogenic variants in the fumarate hydratase (FH) gene, which encodes the enzyme that catalyzes the interconversion of fumarate and L-malate. We utilized enzyme and protein mobility assays to evaluate the FH enzyme in a cohort of patients who showed clinical manifestations of HLRCC but were negative for known pathogenic FH gene variants. FH enzyme activity and protein levels were decreased by 50% or greater in three family members, despite normal FH mRNA expression levels as measured by quantitative PCR. Direct Nanopore RNA sequencing demonstrated 57 base pairs of retained intron sequence between exons 9 and 10 of polyadenylated FH mRNA in these patients, resulting in a truncated FH protein. Genomic sequencing revealed a heterozygous intronic alteration of the FH gene (chr1: 241498239 T/C) resulting in formation of a splice acceptor site near a polypyrimidine tract, and a uterine fibroid obtained from a patient showed loss of heterozygosity at this site. The same intronic FH variant was identified in an unrelated patient who also showed a clinical phenotype of HLRCC. These data demonstrate that careful clinical assessment as well as biochemical characterization of FH enzyme activity, protein expression, direct RNA sequencing, and genomic DNA sequencing of patient-derived cells can identify pathogenic variants outside of the protein coding regions of the FH gene., (Published by Oxford University Press 2023.)

Importance: The differential diagnosis of extensive open comedones includes inherited genetic syndromes and several acquired conditions. Birt-Hogg-Dube syndrome (BHD) is not typically included in the differential diagnosis of syndromes with comedonal lesions. Given the potentially life-threatening systemic complications associated with BHD, early recognition and diagnosis of the condition is important., Observations: We describe comedonal or cystic fibrofolliculomas in 4 patients with BHD. Cutaneous lesions were identified on the face, neck, chest, and abdomen., Conclusions and Relevance: Comedonal or cystic fibrofolliculomas are a variant of fibrofolliculomas that have not previously been well characterized in patients with BHD and represent a novel diagnostic clue to its early detection and diagnosis. Expanding the phenotypic features of BHD facilitates earlier diagnosis of the syndrome, which allows for early surveillance of renal cancer in affected patients as well as disease screening in their relatives.

Unlabelled: Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene., Implications: BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer., (©2013 AACR.)

Purpose: Recently, a new renal cell cancer syndrome has been linked to germline mutation of multiple subunits (SDHB/C/D) of the Krebs cycle enzyme, succinate dehydrogenase. We report our experience with the diagnosis, evaluation and treatment of this novel form of hereditary kidney cancer., Materials and Methods: Patients with suspected hereditary kidney cancer were enrolled on a National Cancer Institute institutional review board approved protocol to study inherited forms of kidney cancer. Individuals from families with germline SDHB, SDHC and SDHD mutations, and kidney cancer underwent comprehensive clinical and genetic evaluation., Results: A total of 14 patients from 12 SDHB mutation families were evaluated. Patients presented with renal cell cancer at an early age (33 years, range 15 to 62), metastatic kidney cancer developed in 4 and some families had no manifestation other than kidney tumors. An additional family with 6 individuals found to have clear cell renal cell cancer that presented at a young average age (47 years, range 40 to 53) was identified with a germline SDHC mutation (R133X) Metastatic disease developed in 2 of these family members. A patient with a history of carotid body paragangliomas and an aggressive form of kidney cancer was evaluated from a family with a germline SDHD mutation., Conclusions: SDH mutation associated renal cell carcinoma can be an aggressive type of kidney cancer, especially in younger individuals. Although detection and management of early tumors is most often associated with a good outcome, based on our initial experience with these patients and our long-term experience with hereditary leiomyomatosis and renal cell carcinoma, we recommend careful surveillance of patients at risk for SDH mutation associated renal cell carcinoma and wide surgical excision of renal tumors., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Kidney cancer is a heterogeneous disease comprised of a number of histologic subtypes, each associated with unique genetic mutations, clinical features, and sensitivity to treatment. By examining families affected with the hereditary kidney cancer syndromes von Hippel-Lindau, hereditary papillary renal cell carcinoma, hereditary leiomyomatosis and renal cell carcinoma, and Birt-Hogg-Dubé, researchers have been able to identify the genes responsible for these syndromes. This work has revealed that kidney cancer is fundamentally a metabolic disorder, and as such, novel targeted therapies specific to their molecular biology have been developed and employed in both the hereditary and sporadic forms of renal cell carcinoma.

Background: von Hippel-Lindau (vHL) disease is an autosomal dominant syndrome associated with neoplasms in multiple organs, which includes the pancreas. Here, we report the greatest single center experience in patients with vHL pancreatic endocrine neoplasm (PNETs)., Methods: Between December 1998 and November 2006, 633 patients with vHL were evaluated and those with PNETs were enrolled on a prospective protocol., Results: Overall, 108 vHL patients had PNETs (17%). Nine patients had metastatic disease (8.3%) from their PNET. Patients with lesions greater than 3 cm (n = 25) were more likely to develop metastases than patients with lesions less than 3 cm (n = 83) (P < .005). Thirty-nine patients underwent resection. Germline sequencing showed that 78% of patients with metastases (7/9) had exon 3 mutations compared with 46% of patients without metastases (32/98; P < .01). Tumor doubling time was calculated for the largest PNET. The group with metastases had an average tumor doubling time of 337 days (range, 180-463 days) compared with 2630 days (range, 103-9614 days) for those without metastases (P < .0001)., Conclusions: By implementing a system of selective operative resection based on defined criteria, vHL patients with PNETs can be managed safely. For patients with small primary lesions (<3 cm), without a mutation of exon 3 and slow tumor doubling time (>500 days), a nonoperative approach may be appropriate for these nonfunctional neoplasms.

Purpose: Hereditary leiomyomatosis and renal cell cancer is a recently described hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and kidney cancer. Our initial experience revealed the aggressive behavior of these renal tumors, often with early metastasis, despite small primary tumor size. We report the clinical characteristics and urological treatment of patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors., Materials and Methods: A total of 19 patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors were evaluated. The 11 women and 8 men had a median age at diagnosis of 39 years (range 22 to 67), and a median clinical and radiological followup of 34 months (range 6 to 141). Hereditary leiomyomatosis and renal cell cancer manifestations in patients with renal tumors included cutaneous leiomyomas in 11 of 17 evaluable patients (65%) and uterine leiomyomas in 7 of 7 evaluable females (100%)., Results: Median pathological tumor size was 7.8 cm (range 1.5 to 20). Histological subtypes were consistent with hereditary leiomyomatosis and renal cell cancer renal carcinoma. Four of 7 patients with 2.0 to 6.7 cm T1 tumors had spread to regional lymph nodes or metastases at nephrectomy. Overall 9 of 19 patients (47%) presented with nodal or distant metastases., Conclusions: Renal tumors in patients with hereditary leiomyomatosis and renal cell cancer syndrome are significantly more aggressive than those in patients with other hereditary renal tumor syndromes. In contrast to other familial renal cancer syndromes, the observation of 3 cm or less renal tumors associated with hereditary leiomyomatosis and renal cell cancer is not recommended. Careful followup of affected and at risk individuals in families is necessary.

Purpose: Familial renal carcinoma is defined as families with 2 or more individuals with renal cell carcinoma without evidence of known hereditary renal carcinoma syndromes. To better characterize this familial cancer we reviewed renal carcinoma families evaluated at the National Cancer Institute between 1990 and 2004 to identify distinctive features of these families. We also determined the risk of renal carcinoma in first-degree relatives of affected family members., Materials and Methods: We evaluated 141 at risk asymptomatic relatives of affected individuals from 50 families with 2 or more members with renal carcinoma. Histology slides of renal tumors from affected family members were reviewed. At risk members from renal carcinoma families were screened for occult renal neoplasms by renal ultrasound and computerized tomography. DNA from select families was tested for germline mutations of known renal carcinoma genes when clinically indicated and constitutional cytogenetic analysis was performed to search for germline chromosome alterations., Results: Familial renal carcinoma families could be subdivided into subtypes based on tumor multiplicity and renal tumor histology. Of 141 at risk members of renal carcinoma families screened for occult renal tumors 2 were found to have occult renal tumors, which were identified as renal oncocytoma and a solid tumor that was not resected, respectively. No histologically confirmed occult renal carcinomas were detected in at risk family members. Several families previously classified as having familial renal carcinoma were found on further evaluation to have hereditary renal cancer syndromes., Conclusions: Familial renal carcinoma is a heterogeneous clinical and pathological entity. Familial renal carcinoma was subdivided into groups based on tumor multiplicity and tumor pathology. The empirical risk of histologically documented renal carcinoma in first-degree relatives who were members of familial renal carcinoma families was less than 1:141. One renal oncocytoma and 1 small solid renal tumor were detected.

Purpose: Hereditary papillary renal carcinoma (HPRC) is characterized by a predisposition to multiple, bilateral papillary type 1 renal tumors caused by inherited activating missense mutations in the tyrosine kinase domain of the MET proto-oncogene. In the current study we evaluated the clinical phenotype and germline MET mutation of 3 new HPRC families. We describe the early onset clinical features of HPRC., Materials and Methods: We identified new HPRC families of Italian (family 177), Spanish (family 223) and Cuban (family 268) descent. We evaluated their clinical features, performed MET mutation analysis by denaturing high performance liquid chromatography and DNA sequencing, and estimated age dependent penetrance and survival using Kaplan-Meier analysis. We characterized renal tumors by histology and fluorescence in situ hybridization., Results: Identical germline MET c.3522G --> A mutations (V1110I) were identified in families 177 and 268 but no evidence of a founder effect was found. Affected members of family 223 carried a germline c.3906G --> C.3522G --> A MET mutation (V1238I). Age dependent penetrance but not survival was significantly earlier for the c.3522G -->A mutation than for the c.3906G --> A mutation in these HPRC families. Trisomy of chromosome 7 and papillary renal carcinoma type 1 histology were detected in papillary renal tumors., Conclusions: HPRC can occur in an early onset form. The median age for renal tumor development in these 3 HPRC families was 46 to 63 years. HPRC associated papillary renal tumors may be aggressive and metastasize, leading to mortality. Median survival age was 60 to 70 years. Families with identical germline mutations in MET do not always share a common ancestor. HPRC is characterized by germline mutations in MET and papillary type 1 renal tumor histology.

The use of professional portfolios, comprised of a wide variety of materials and evidence to profile the scope and depth of a clinician's practice competence, is gaining popularity. The usual methods of showing professional competence via paper and pencil/computerized testing, oral presentations, or performance observations provide a picture of competence at a given point in time based on didactic content recall. Portfolios present an opportunity for presentation of a larger number of competency evaluation points. Although examinations can be validated with psychometrics, providing accuracy and reliability of evaluation of portfolios is a more complicated matter. This article discusses the experiences of the Credentialing Committee of the International Society of Nurses in Genetics as they created and validated the evaluation of professional portfolios to provide a quality credential for nurses in genetics., (Copyright Elsevier Inc. All rights reserved.)

Knowledge gained from the Human Genome Project and related genetic research is already impacting clinical oncology nursing practice. Because cancer is now understood to be a genetic disease, changes in the traditional approaches to prevention, diagnosis, and therapeutic management of cancer are becoming increasingly genetically based. Therefore, to ensure competency in oncology nursing practice at all levels, nurses must incorporate an understanding of the underlying biology of carcinogenesis and the molecular rationale underlying strategies to prevent, diagnose, and treat cancer.

The information gained from the Human Genome Project and related genetic research will undoubtedly create significant changes in healthcare practice. It is becoming increasingly clear that nurses in all areas of clinical practice will require a fundamental understanding of basic genetics. This article provides the oncology nurse with an overview of basic genetic concepts, including inheritance patterns of single gene conditions, pedigree construction, chromosome aberrations, and the multifactorial basis underlying the common diseases of adulthood. Normal gene structure and function are introduced and the biochemistry of genetic errors is described.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, histologically benign splenomegaly and generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation. ALPS has been attributed to defective programmed cell death of lymphocytes, most often arising as a result of mutations in the gene encoding the lymphocyte apoptosis receptor Fas/APO-l/CD95. We identified a novel mutation in the intracellular apoptosis signaling domain of Fas in 11 members of a family, individual members of which have been monitored for up to 25 years, with 1 or more features of ALPS. This study of a large number of family members carrying the same Fas defect demonstrates that ALPS is inherited in an autosomal dominant fashion but with a high degree of variability in clinical expression. Although 1 affected individual died of postsplenectomy sepsis and 1 has been treated for lymphoma, the Fas mutation in this family has been compatible with a healthy adulthood, as clinical features of ALPS have receded with increasing age.

IL2RG, the gene encoding the common gamma chain, gamma c, of the receptor for interleukin-2 and other cytokines, has been identified as the disease gene for severe combined immunodeficiency (SCID) of the X-linked type. Specific mutational diagnosis for X-linked SCID has thus become possible. For many women at risk for carrying an IL2RG mutation, no samples were saved from an affected male relative prior to either death or bone marrow transplantation (BMT). To establish optimal methods for genetic evaluation of such women, we compared mutational screening by single-strand conformational polymorphism, heteroduplex analysis and dideoxy fingerprinting (ddF). Abnormally migrating band patterns were followed up with direct sequencing for identification of specific mutations. The most sensitive method, ddF, detected heterozygous alterations, subsequently confirmed to represent significant mutations, in all of 19 unrelated obligate or suspected carriers studied. Some of these women, as well as others at risk for carrying an X-linked SCID mutation, enrolled in a study of prenatal diagnosis after fetal testing for gender determination. Originally using linkage analysis and, more recently, specific detection of IL2RG mutations, we evaluated pregnancies at risk for X-linked SCID prospectively on a research basis. Of 27 male fetuses tested 14 were predicted to be unaffected and confirmed to have normal immune status at birth. Among pregnancies predicted to be affected, 2 were terminated, while 11 affected males were born at term. Nine of these received neonatal BMT, one had BMT at 3 months of age, and one underwent a successful experimental in utero BMT. In our study cohort accurate prenatal diagnosis assisted decision making and expanded treatment options for families at risk for having infants with a severe, but treatable genetic disorder that presents early in life.

The information gained from the Human Genome Project and related genetic research will undoubtedly create significant changes in health care practice. It is becoming increasing clear that nurses in all areas of clinical practice will require a fundamental understanding of basic genetics. This self-learning module provides the oncology nurse with an overview of basic genetic concepts including inheritance patterns of single gene conditions, pedigree construction, chromosome aberrations, and the multifactorial basis underlying many common diseases of adulthood. Normal gene structure and function will be introduced and the biochemistry of genetic errors will be described.

Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4- CD8- T cells that express the alpha/beta T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS.