Cryptic splice mutation in the fumarate hydratase gene in patients with clinical manifestations of Hereditary Leiomyomatosis and Renal Cell Cancer.

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.

A diagnosis of Birt-Hogg-Dubé syndrome in individuals with Smith-Magenis syndrome: Recommendation for cancer screening.

We report a series of four unrelated adults with Smith-Magenis syndrome (SMS) and concomitant features of Birt-Hogg-Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.

Comprehensive characterization of Alu-mediated breakpoints in germline VHL gene deletions and rearrangements in patients from 71 VHL families.

Von Hippel-Lindau (VHL) is a hereditary multisystem disorder caused by germline alterations in the VHL gene. VHL patients are at risk for benign as well as malignant lesions in multiple organs including kidney, adrenal, pancreas, the central nervous system, retina, endolymphatic sac of the ear, epididymis, and broad ligament. An estimated 30%-35% of all families with VHL inherit a germline deletion of one, two, or all three exons. In this study, we have extensively characterized germline deletions identified in patients from 71 VHL families managed at the National Cancer Institute, including 59 partial (PD) and 12 complete VHL deletions (CD). Deletions that ranged in size from 1.09 to 355 kb. Fifty-eight deletions (55 PD and 3 CD) have been mapped to the exact breakpoints. Ninety-five percent (55 of 58) of mapped deletions involve Alu repeats at both breakpoints. Several novel classes of deletions were identified in this cohort, including two cases that have complex rearrangements involving both deletion and inversion, two cases with inserted extra Alu-like sequences, six cases that involve breakpoints in Alu repeats situated in opposite orientations, and a "hotspot" PD of Exon 3 observed in 12 families that involves the same pair of Alu repeats.

Comprehensive genomic and phenotypic characterization of germline FH deletion in hereditary leiomyomatosis and renal cell carcinoma.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a familial cancer syndrome associated with the development of cutaneous and uterine leiomyomas, and an aggressive form of type 2 papillary kidney cancer. HLRCC is characterized by germline mutation of the FH gene. This study evaluated the prevalence and clinical phenotype of FH deletions in HLRCC patients. Patients with phenotypic manifestations consistent with HLRCC who lacked detectable germline FH intragenic mutations were investigated for FH deletion. A series of 28 patients from 13 families were evaluated using a combination of a comparative genomic hybridization (CGH) array and/or CLIA-approved FH deletion/duplication analyses. Thirteen distinct germline deletions were identified in the 13 UOB families, including 11 complete FH gene deletions and 2 partial FH gene deletions. The size of eight evaluated complete FH deletions varied from ∼4.74 Mb to 249 kb, with all deletions resulting in additional gene losses. Two partial FH gene deletions were identified, with one resulting in loss of exon 1 and the upstream region of the FH gene only. Kidney cancer was diagnosed in 9 (32%) of 28 patients and 7 (54%) of 13 families possessing either complete or partial FH deletions. Cutaneous and uterine leiomyomas were observed at similar rates to those in FH point mutation families. Complete or partial FH gene alterations in HLRCC families are associated with all of the canonical HLRCC manifestations, including type 2 papillary kidney cancer and should be screened for in any patient at-risk for this disorder.

Germline PTEN mutation Cowden syndrome: an underappreciated form of hereditary kidney cancer.

PURPOSE: Cowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma. MATERIALS AND METHODS: Patients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity. RESULTS: Among 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies. CONCLUSIONS: Renal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.

Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer.

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.

Impact of genetics on the diagnosis and treatment of renal cancer.

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.

CDC73 Germline Mutation in a Family With Mixed Epithelial and Stromal Tumors.

OBJECTIVE: To describe a family in which 3 members presented with mixed epithelial tumor of the kidney (MEST) and were found to possess a germline mutation in CDC73, a gene which is associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT). MATERIALS AND METHODS: Blood and tumor DNA from three family members who presented with a primary diagnosis of MEST was subjected to targeted gene sequencing to identify potential genetic components. RESULTS: A germline start codon mutation (p.M1I) in CDC73 was identified in all 3 family members who presented with MEST and 2 tumors from 1 patient demonstrated somatic copy-neutral loss of heterozygosity. Patients presented with no evidence of hyperparathyroidism or jaw tumors, but both female patients had hysterectomies at an early age due to excessive bleeding and numerous fibroids, which is common in HPT-JT. A germline p.M1I mutation has been previously reported in a family with clinical features of HPT-JT. CONCLUSION: Patients with MEST may be at risk for HPT-JT and CDC73 germline mutation testing of MEST patients should be considered.

Comedonal and Cystic Fibrofolliculomas in Birt-Hogg-Dube Syndrome.

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.

Efficacy of Intralesional Botulinum Toxin A for Treatment of Painful Cutaneous Leiomyomas: A Randomized Clinical Trial.

IMPORTANCE: Cutaneous leiomyomas can be associated with severe paroxysmal pain in which nerve conduction may have a key role. Medical management of painful cutaneous leiomyomas is generally unsatisfactory. OBJECTIVE: To assess the efficacy of intralesional botulinum toxin A in the management of pain associated with cutaneous leiomyomas. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled pilot study conducted from January 5, 2009, to March 27, 2014. The setting was a single-center study at the National Institutes of Health among participants 18 years or older with cutaneous leiomyomas characterized by pain at least once weekly and pain of at least 4 on a pain scale ranging from 0 to 10. INTERVENTIONS: Eighteen participants were randomized to receive intralesional botulinum toxin A (5 U per 1 cm2) or equivalent volumes of intralesional saline placebo. MAIN OUTCOMES AND MEASURES: The primary outcomes were the differences in average lesional pain assessed by the Brief Pain Inventory and visual analog scale before and after ice provocation over a 4-week period. RESULTS: No significant difference in average lesional pain was observed between the study arms. Decreased pain was reported in the botulinum toxin vs placebo arms by visual analog scale scores before ice provocation (median, 0.00; range, -3.30 to 0.70 for botulinum toxin and median, 0.40; range, -1.30 to 1.50 for placebo; P = .06); however, this finding was nonsignificant. No significant difference was observed in change in pain after ice provocation. A significant difference was seen between the arms in skin-related quality of life by total Dermatology Life Quality Index (median, -4.00; range, -8.00 to 2.00 for botulinum toxin and median, 0.00; range, -1.00 to 4.00 for placebo; P = .007) and with the specific skin pain-related question on the Dermatology Life Quality Index (median, -1.00; range, -2.00 to 1.00 for botulinum toxin and median, 0.00; range, -1.00 to 0.00 for placebo; P = .048). No significant difference was found in pain as ascertained by Patient Global Impression of Change at week 4. No serious adverse events related to botulinum toxin use were observed. CONCLUSIONS AND RELEVANCE: The use of botulinum toxin to treat painful cutaneous leiomyomas was associated with improved quality of life and with a trend toward improved pain at rest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00971620.

The role of the nurse in cancer genetics.

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.

Portfolio evaluation for professional competence: credentialing in genetics for nurses.

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.

Inherited urologic malignant disorders: nursing implications.

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.

Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition in which susceptible individuals are at risk for the development of cutaneous leiomyomas, early onset multiple uterine leiomyomas and an aggressive form of type 2 papillary renal cell cancer. HLRCC is caused by germline mutations in the fumarate hydratase (FH) gene which inactivate the enzyme and alters the function of the tricarboxylic acid (Krebs) cycle. Issues surrounding surveillance and treatment for HLRCC-associated renal cell cancer were considered as part of a recent international symposium on HLRCC. The management protocol proposed in this article is based on a literature review and a consensus meeting. The lifetime renal cancer risk for FH mutation carriers is estimated to be 15 %. In view of the potential for early onset of RCC in HLRCC, periodic renal imaging and, when available, predictive testing for a FH mutation is recommended from 8 to 10 years of age. However, the small risk of renal cell cancer in the 10-20 years age range and the potential drawbacks of screening should be carefully discussed on an individual basis. Surveillance preferably consists of annual abdominal MRI. Treatment of renal tumours should be prompt and generally consist of wide-margin surgical excision and consideration of retroperitoneal lymph node dissection. The choice for systemic treatment in metastatic disease should, if possible, be part of a clinical trial. Screening procedures in HLRCC families should preferably be evaluated in large cohorts of families.

Birt-Hogg-Dubé: beyond the clinical manifestations.

Clinicians and scientists understand the medical implications of BHD; however, what may not be apparent to clinicians and scientists are the psycho-social aspects of living with BHD. Although medical reality differs among people who have Birt-Hogg-Dubé, they often share multiple non-medical ramifications ranging from economic and physical insecurity to interruptions in familial communication patterns and relationships. Physicians cognizant of the psycho-social aspects of having BHD are in a position to offer enhanced and meaningful non-medical interventions and care to their patient with BHD.

Diagnosis and management of BHD-associated kidney cancer.

In addition to the associated cutaneous and pulmonary manifestations, individuals with the Birt-Hogg-Dubé (BHD) syndrome have an increased risk of developing kidney cancer, which is often bilateral and multifocal. The risk of developing a renal tumor in this population does not decrease with age and therefore warrants a lifelong screening approach. We recommend abdominal imaging every 36 months in individuals without renal lesions at initial screening. Once renal tumors are identified, they should be followed with interval imaging studies until the largest tumor reaches 3 cm in maximal diameter, at which point nephron-sparing surgery should be ideally pursued. While the histology of renal tumors can vary in the BHD syndrome, most tumors possess a relatively indolent natural history and do not require adjuvant therapy if resected when localized to the kidney. With this approach, the vast majority of patients will achieve a curative oncologic outcome and avoid the medical sequelae of chronic renal insufficiency that could otherwise result from total nephrectomy.

A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma.

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.

Familial renal carcinoma: clinical evaluation, clinical subtypes and risk of renal carcinoma development.

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.

Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer.

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.

Clinical, genetic and radiographic analysis of 108 patients with von Hippel-Lindau disease (VHL) manifested by pancreatic neuroendocrine neoplasms (PNETs).

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.