Bap1 Tumor Predisposition Syndrome
Summary
Clinical characteristics.
BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for a specific skin lesion, BAP1-inactivated melanocytic tumors (BIMT; formerly called atypical Spitz tumors), and the following cancers, in descending order of frequency: uveal (eye) melanoma (UM), malignant mesothelioma (MMe), cutaneous melanoma (CM), renal cell carcinoma (RCC), and basal cell carcinoma (BCC). Hepatocellular carcinoma, cholangiocarcinoma, and meningioma may also be associated with BAP1-TPDS. Affected individuals can have more than one type of primary cancer. In general, the median age of onset of these tumors is younger than in the general population. UM tends to be a more aggressive class 2 tumor with higher risk for metastasis and reduced survival compared to UM occurring in the general population. Due to the limited number of families reported to date, the penetrance, natural history, and frequencies of BAP1-associated tumors are yet to be determined. Other suspected but unconfirmed tumors in BAP1-TPDS include (in alphabetic order): breast cancer, neuroendocrine carcinoma, non-small-cell lung adenocarcinoma, thyroid cancer, and urinary bladder cancer.
Diagnosis/testing.
The diagnosis of BAP1-TPDS is established in a proband by identification of a heterozygous germline pathogenic variant in BAP1 on molecular genetic testing.
Management.
Treatment of manifestations: Treatment of CM and BCC per established clinical guidelines. UM: because of the increased aggressiveness of BAP1-related UM, management should be the same as the more aggressive class 2 or monosomy 3 tumors. MMe treatment per oncologist familiar with BAP1-MMe; RCC treatment per established management guidelines.
Prevention of primary manifestations: UM: avoid arc-welding. MMe: avoid asbestos exposure (including naturally occurring tremolite and erionite) and smoking. CM and BCC: limit sun exposure, use sunscreen and protective clothing, and have regular dermatologic examinations.
Surveillance: BIMT, CM, BCC: annual full-body dermatologic examinations beginning around age 18 years. Baseline whole-body imaging in those with a large number of lesions; repeat as needed. Biopsy of BIMT is not recommended unless lesions grow or change in shape or color. UM: yearly dilated eye examinations and at least baseline fundus imaging beginning around age 11 years. Refer any pigmented intraocular lesion to an ocular oncologist for follow up and management. MMe: no screening modalities exist; however, annual physical examination is recommended. If an abdominal MRI is to be performed as recommended for RCC, consider evaluation of the peritoneum and pleura as well. While some physicians recommend spiral chest CT for asymptomatic persons with a history of exposure to asbestos, others do not, given the possible increased risk of cancer from radiation exposure. RCC: annual clinical examination; abdominal ultrasound every two years alternating with MRI every two years starting at age 30 years.
Agents/circumstances to avoid: Arc welding, asbestos including naturally occurring tremolite and erionite, smoking, unnecessary and prolonged sun exposure, routine chest x-ray and CT examinations.
Evaluation of relatives at risk: Clarify the genetic status of at-risk relatives by molecular genetic testing for the BAP1 pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of screening and preventive measures.
Genetic counseling.
BAP1-TPDS is inherited in an autosomal dominant manner. To date, most individuals diagnosed with BAP1-TPDS have an affected parent; the proportion of BAP1-TPDS caused by a de novo pathogenic variant is unknown. Each child of an individual with BAP1-TPDS has a 50% chance of inheriting the BAP1 pathogenic variant; however, penetrance appears to be incomplete and the types of BAP1-related tumors can vary among different members of the same family. Once the germline BAP1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Diagnosis
No diagnostic criteria have been published for the BAP1 tumor predisposition syndrome (BAP1-TPDS). In one review, 90% of families reported with a germline BAP1 pathogenic variant met the criteria outlined in Suggestive Findings [Rai et al 2016].
Suggestive Findings
BAP1-TPDS should be suspected in an individual who has EITHER of the following:
- Two or more confirmed BAP1-TPDS tumors*
- One BAP1-TPDS tumor and a first- or second-degree relative with a confirmed BAP1-TPDS tumor*
* Excluding two basal cell cancers and/or cutaneous melanomas, given their high frequency in the general population
Confirmed BAP1-TPDS tumors include the following (in descending order of likelihood):
- BAP1-inactivated melanocytic tumors (BIMT). Formerly called atypical Spitz tumors, these may be the most common manifestation of BAP1-TPDS, and may result in the initial identification of a proband. BIMT are skin colored to reddish brown, averaging 5 mm in diameter; the histologic findings are between those of a Spitz nevus and a melanoma. Both copies of BAP1 are inactivated, leading to loss of staining for the BAP1 protein on immunohistochemistry; in addition, BIMT usually have somatic BRAF pathogenic variant p.Val600Glu.
- Uveal (eye) melanoma (UM)
- Malignant mesothelioma (MMe)
- Cutaneous melanoma (CM)
- Renal cell carcinoma (RCC)
- Basal cell carcinoma (BCC)
- Hepatocellular carcinoma, cholangiocarcinoma, and meningioma. These now appear to be less common manifestations of BAP1-TPDS.
Unconfirmed tumors (with conflicting evidence regarding inclusion in the BAP1-TPDS spectrum) include the following (in alphabetic order):
- Breast cancer
- Neuroendocrine tumors
- Non-small-cell lung adenocarcinoma
- Thyroid cancer
- Urinary bladder cancer
Establishing the Diagnosis
The diagnosis of BAP1-TPDS is established in a proband by identification of a heterozygous germline pathogenic variant in BAP1 on molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of BAP1 is performed. The identification of partial and whole-gene deletions in a subset of individuals supports the benefit of doing gene-targeted deletion/duplication analysis concurrently, or if no BAP1 pathogenic variant is found on sequence analysis.
- A multigene panel that includes BAP1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in BAP1 Tumor Predisposition Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| BAP1 | Sequence analysis 3 | >87.5% 4 |
| Gene-targeted deletion/duplication analysis 5 | <12.5% 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Haugh et al [2017], Carlo et al [2018], Huang et al [2018], Walpole et al [2018], Boru et al [2019]
Clinical Characteristics
Clinical Description
BAP1 tumor predisposition syndrome (BAP1-TPDS) is associated with increased risk for a number of cancers and a specific skin lesion, BAP1-inactivated melanocytic tumor (BIMT; formerly called atypical Spitz tumor). Affected individuals can have more than one type of primary cancer [Abdel-Rahman et al 2011, Testa et al 2011, Wiesner et al 2011, Popova et al 2013, Walpole et al 2018].
Because of the limited number of families reported to date and ascertainment bias of groups focusing on uveal melanoma, malignant mesothelioma, and cutaneous melanoma, the penetrance and frequencies of the various BAP1-associated tumors are yet to be determined. In an attempt to adjust for ascertainment bias, Walpole et al [2018] (as noted below) compared the prevalence of each component tumor in probands with BAP1-TPDS to the prevalence in relatives known to also have a BAP1 pathogenic variant. It has been well established, however, that the following tumor types are associated with BAP1-TPDS.
BAP1-inactivated melanocytic tumor (BIMT; formerly called atypical Spitz tumor). The natural history of these lesions is not clearly known. It appears that individuals with BAP1-TPDS typically have multiple lesions [Haugh et al 2017]. BIMT are skin colored to reddish brown, averaging 5 mm in diameter; the histologic findings are between those of a Spitz nevus and a melanoma. Both copies of BAP1 are inactivated, leading to loss of staining for the BAP1 protein on immunohistochemistry; in addition, BIMT usually have somatic BRAF pathogenic variant p.Val600Glu.
Uveal melanoma (UM) is the cancer most commonly reported in persons with BAP1-TPDS (36% of probands and 16% of relatives reported with BAP1-TPDS have UM), and it is the cancer with the earliest reported age of diagnosis (age 16 years) [Walpole et al 2018]. Median age of onset of UM in persons with BAP1-TPDS is 53 years, which is younger than the onset of UM in the general population (62 years). The tumors are generally more aggressive class 2 (i.e., high metastatic risk) tumors with reduced survival [Njauw et al 2012, Rai et al 2016]. In one study, mean length of survival in persons whose UM lacked BAP1 expression was 4.74 years compared to 9.97 years in persons whose tumors expressed BAP1 [Kalirai et al 2014].
Malignant mesothelioma (MMe) is the second most frequent cancer (25% of probands and 19% of relatives) identified in individuals with BAP1-TPDS [Walpole et al 2018]. Several studies have shown that the median age of onset of MMe in individuals with BAP1-TPDS was significantly earlier (55 to 58 years) than that of sporadic MMe (68-72 years) [Baumann et al 2015, Ohar et al 2016, Walpole et al 2018]. In the general population, pleural MMe accounts for about 80% and peritoneal MMe constitutes most of the remaining MMe. However, in individuals with BAP1-TPDS the ratio of peritoneal to pleural involvement is significantly higher [Carbone et al 2015, Cheung et al 2015, Ohar et al 2016, Walpole et al 2018]. In BAP1-TPDS the majority of peritoneal MMe occurs in women, in contrast to the general population, in which men are more likely to have this tumor type [Walpole et al 2018].
In contrast to survival in persons with BAP1-related cutaneous melanoma, UM, or renal cell carcinoma, survival in persons with BAP1-related MMe may be significantly longer, especially in those with pleural mesothelioma [Baumann et al 2015, Pastorino et al 2018, Wang et al 2018, Hassan et al 2019].
Growing evidence suggests that BAP1 pathogenic variants interact with environmental asbestos exposure to increase the risk for MMe [Xu et al 2014, Kadariya et al 2016].
Cutaneous melanoma (CM). First reported in association with BAP1-TPDS in 2011, CM is now known to be the third most common cancer in BAP1-TPDS, occurring in 13% of affected individuals [Wiesner et al 2011]. Interestingly, Walpole et al [2018] found CM in 45% of probands but in no relatives affected with BAP1-TPDS [Walpole et al 2018]. Multiple primary cutaneous melanomas are common. The median age of onset of CM in individuals with BAP1-TPDS is earlier than in the general population (39 vs 58 years). While it is possible that BAP1-related CM is more aggressive than CM in the general population, the data are currently inconsistent [Gupta et al 2015, Kumar et al 2015, Rai et al 2016, Liu-Smith & Lu 2020].
Renal cell carcinoma (RCC). Heterozygous BAP1 germline pathogenic variants are specifically associated with an increased risk for RCC, in particular those with clear cell morphology [Haas & Nathanson 2014]. Walpole et al [2018] found RCC in 10% of probands and relatives with BAP1-TPDS, although the specific histology was not always known and additional morphologies including papillary and chromophobe cell tumors were also observed. Median age of RCC diagnosis appears to be younger in persons with BAP1-TPDS than in the general population (47-50 vs 64 years), and length of survival is decreased in persons with BAP1-related RCC [Rai et al 2016]. Histology of these tumors is distinct from tumors not associated with pathogenic variants in BAP1, with higher grade at diagnosis and lack of somatic PBRM1 pathogenic variants (which are common in RCC not associated with pathogenic variants in BAP1) [Peña-Llopis et al 2012].
Basal cell carcinoma (BCC) has recently been confirmed as a tumor in the BAP1-TPDS spectrum [de la Fouchardière et al 2015b, Mochel et al 2015, Wadt et al 2015]. Multiple primary basal cell carcinomas are common. Walpole et al [2018] found that the median age of diagnosis for non-melanoma skin cancer (primarily BCC) was 44 years.
Meningioma, particularly a high-grade rhabdoid subtype, has been suggested to be associated with BAP1-TPDS [Abdel-Rahman et al 2011, Cheung et al 2015, de la Fouchardière et al 2015a, Wadt et al 2015, Shankar et al 2017]. This is further supported by identification of this tumor in 8.5% of probands with BAP1-TPDS and 2.2% of relatives with the BAP1 pathogenic variant.
Cholangiocarcinoma has also been suggested to be part of BAP1-TPDS [Njauw et al 2012, Pilarski et al 2014, Wadt et al 2015]. Walpole et al [2018] found this cancer in 1.4% of probands with BAP1-TPDS but in none of the relatives.
Hepatocellular carcinoma (HCC). Germline BAP1 pathogenic variants have been observed in 0.5% of unselected individuals with HCC [Huang et al 2018]. Walpole et al [2018] identified HCC in 0.7% of probands with BAP1-TPDS and 1.6% of relatives with the BAP1 pathogenic variant.
Other cancers with some evidence (although inconsistent) supporting inclusion in the BAP1-TPDS spectrum are the following (in alphabetic order):
- Breast cancer [Testa et al 2011, Njauw at al 2012, Popova et al 2013, Abdel-Rahman et al 2016]. Although breast cancer has been reported in individuals with germline pathogenic variants in BAP1, in one individual biallelic inactivation was not observed in the tumor tissue. In addition, no BAP1 pathogenic variants were detected in any of the 1,078 breast cancers included in The Cancer Genome Atlas (TCGA) project, suggesting that breast cancer is likely not part of the phenotype.
- Neuroendocrine tumors [Abdel-Rahman et al 2011, Wadt et al 2012]
- Non-small-cell lung adenocarcinoma [Abdel-Rahman et al 2011, Njauw et al 2012, Wadt et al 2012, Aoude et al 2013b]
- Thyroid cancer [Popova et al 2013, McDonnell et al 2016]
- Urinary bladder carcinoma. One individual was reported with a BAP1 germline pathogenic variant and evidence of biallelic inactivation in the tumor [Tesch et al 2020].
Genotype-Phenotype Correlations
To date no genotype-phenotype correlations for BAP1-TPDS have been published.
Most families (104 of 141) have had a unique BAP1 pathogenic variant; a number of recurrent pathogenic variants have been reported [Walpole et al 2018] (see Molecular Genetics).
Penetrance
The penetrance of the BAP1-TPDS appears to be high based on the published literature, with 88% of probands and 82.5% of relatives with a heterozygous germline BAP1 pathogenic variant having had a cancer diagnosis. However, ascertainment biases in favor of both testing and reporting affected versus unaffected individuals may have inflated this figure. For example, in more than half of the reported families only the proband had been tested. Also, the majority of the study participants were ascertained based on their strong family history of cancer. Given these biases, an accurate estimate of penetrance cannot be determined at this time. In attempting to adjust for this, Walpole et al [2018] found a significantly lower prevalence of BAP1-related tumors in affected relatives compared to probands (see Prevalence).
Nomenclature
BAP1-inactivated melanocytic tumors have also been called the following:
- Atypical Spitz tumors
- Nevoid melanoma-like melanocytic proliferations (NEMMP) [Njauw et al 2012]
- Melanocytic BAP1-mutated atypical intradermal tumors (MBAITS) [Carbone et al 2012]
- BAPoma [Author, personal observation]
Prevalence
The prevalence of BAP1-TPDS is unknown. Based on data from the Genome Aggregation Database (gnomAD), the carrier frequency is 1:26,837 in the general population. In the cancer cohort from the TCGA, the frequency was 8:10,389 (1:1,299).
The prevalence of BAP1-TPDS ranges from 1%-2% in persons with UM,1%-3% in persons with MMe [Huang et al 2018, Panou et al 2018], 1%-1.5% in those with RCC [Carlo et al 2018, Wu et al 2019], and 0.5% in persons with HCC. Several large studies showed that BAP1-TPDS is rare in those with CM (0.1%) [Aoude et al 2015, O'Shea et al 2017]. The prevalence of BAP1-TPDS in persons with other cancers is unknown.
UM. The prevalence of germline BAP1 pathogenic variants in unselected individuals with UM is 1%-2% [Aoude et al 2013a, Gupta et al 2015, Repo et al 2019]; in contrast, the frequency is 20%-30% in persons with UM who have a family history of UM [Turunen et al 2016, Rai et al 2017].
MMe. Germline BAP1 pathogenic variants have been identified in 1%-3% of simplex cases and 6%-7.7% (9:153) of individuals with familial MMe [Betti et al 2015, Ohar et al 2016, Betti et al 2018].
CM. Germline BAP1 pathogenic variants were observed rarely in two large studies of sporadic CM with a prevalence of 3:1,197 (0.25%) and 0:1109 [Aoude et al 2015, O'Shea et al 2017]. Also, germline BAP1 pathogenic variants are rare in familial CM (0%-0.7%), particularly in those with no other cancers observed in the family [Njauw et al 2012, Boru et al 2019, Potjer et al 2019].
Differential Diagnosis
Pathogenic variants in genes other than BAP1 can be associated with uveal melanoma, cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma; however, no other gene is known to be associated with increased risk for the combination of these cancers, as is seen in BAP1 tumor predisposition syndrome (BAP1-TPDS).
Table 2.
Genes to Consider in the Differential Diagnosis BAP1 Tumor Predisposition Syndrome
| Cancer Type | Gene / Genetic Mechanism | Comments/References |
|---|---|---|
| Uveal melanoma | BRCA1 BRCA2 MBD4 PALB2 | Sinilnikova et al [1999], Iscovich et al [2002], Scott et al [2002], Moran et al [2012], Abdel-Rahman et al [2020a], Abdel-Rahman et al [2020b] |
| Malignant mesothelioma | CDKN2A 1 | Panou et al [2018] |
| Cutaneous melanoma | CDKN2A CDK4 MC1R MITF | Pancreatic cancer is assoc w/CDKN2A pathogenic variants [Marzuka-Alcalá et al 2014]. |
| Hereditary renal cell carcinoma | VHL | See Von Hippel-Lindau Syndrome. |
| Xp11 translocation | Xp11 translocation renal cell carcinoma (OMIM 300854) | |
| FH | Hereditary cutaneous leiomyomatosis, renal cell cancer, uterine leiomyomas (fibroids); see FH Tumor Predisposition Syndrome. | |
| FLCN |
| |
| MET | Hereditary papillary renal cell carcinoma (OMIM 605074) |
Monogenic disorders included in this table are inherited in an autosomal dominant manner.
- 1.
Panou et al [2018] describe several additional genes; however, only BAP1 and CDKN2A remain significant if the Bonferroni correction is applied.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with BAP1 tumor predisposition syndrome (BAP1-TPDS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended in a multidisciplinary team approach [Rai et al 2016, Star et al 2018].
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with BAP1 Tumor Predisposition Syndrome
| System/ Concern | Evaluation | Comment |
|---|---|---|
| BIMT, CM, &/or BCC |
| Beginning at age ~18 yrs |
| UM |
| Beginning at age ~11 yrs |
| MMe |
|
|
| RCC | Abdominal exam & investigation of any suspected symptoms |
|
| Genetic counseling | By genetics professionals 1 | To inform affected persons & their families re nature, MOI, & implications of BAP1-TPDS to facilitate medical & personal decision making |
BIMT = BAP1-inactivated melanocytic tumor; CM = cutaneous melanoma; BCC = basal cell carcinoma; RCC = renal cell carcinoma; MMe = malignant mesothelioma; MOI = mode of inheritance; UM = uveal melanoma
- 1.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations
The treatments for BAP1-TPDS tumors are those used in standard practice.
Table 4.
Treatment of Manifestations in Individuals with BAP1 Tumor Predisposition Syndrome
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| BIMT, CM, &/or BCC |
| Excision biopsy of BIMT is suggested but not universally recommended for asymptomatic, stable lesions [Star et al 2018]. |
| UM | Manage UMs as more aggressive tumors (i.e., those determined to be Class 2 by expression profiling & those w/monosomy 3) | Because of ↑ aggressiveness of BAP1-related UM [Njauw et al 2012] |
| MMe | Treatment per oncologist familiar with BAP1-MMe |
|
| RCC | Treatment per established management guidelines | Several clinical trials incl w/PARP inhibitor are ongoing. |
BIMT = BAP1-inactivated melanocytic tumor; CM = cutaneous melanoma; BCC = basal cell carcinoma; RCC = renal cell carcinoma; MMe = malignant mesothelioma; PARP = poly ADP ribose polymerase; UM = uveal melanoma
Prevention of Primary Manifestations
Uveal melanoma (UM). Arc welding has been associated with risk of UM and this should be avoided if possible.
Sunglasses with high UVA and UVB protection can reduce risk of cancer on the eyelids, but data regarding the benefit of sunglasses for UM are lacking.
Malignant mesothelioma. As with all individuals, asbestos exposure (including naturally occurring tremolite and erionite) and smoking should be avoided.
Cutaneous melanoma (CM). Primary prevention is limited to those measures typically used to reduce the risk for CM, including limiting of sun exposure, regular use of sunscreen and protective clothing, and regular dermatologic examinations.
Surveillance
Consensus management recommendations have not been established; however, several groups have proposed variations of the following (see Table 5) [Carbone et al 2012, Battaglia 2014, Rai et al 2016, Star et al 2018].
Table 5.
Recommended Surveillance for Individuals with BAP1 Tumor Predisposition Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| BIMT, CM, &/or BCC |
| Annually beginning at age ~18 yrs |
| UM |
| Annually beginning at age ~11 yrs |
| MMe (pleural & peritoneal) |
|
|
| RCC |
|
|
BIMT = BAP1-inactivated melanocytic tumor; CM = cutaneous melanoma; BCC = basal cell carcinoma; RCC = renal cell carcinoma; MMe = malignant mesothelioma; UM = uveal melanoma
Agents/Circumstances to Avoid
Avoid the following:
- Arc welding
- Asbestos
- Smoking
- Unnecessary and prolonged sun exposure
- Routine chest x-ray and CT examinations
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of at-risk relatives of an affected individual by molecular genetic testing for the BAP1 pathogenic variant in the family. Family members who have a BAP1 pathogenic variant should be offered regular lifelong surveillance. Family members who have not inherited the pathogenic variant and their subsequent offspring have risks similar to the general population.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Currently no open treatment trials specifically target individuals with BAP1-TPDS, but several trials are currently open for individuals with somatic BAP1 pathogenic variants, including PARP inhibitor therapies as single or combination therapies.
One NCI-sponsored trial using vorinostat in the treatment of metastatic uveal melanoma is assessing BAP1 mutation status as a secondary outcome measure.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.