Genitourinary Cancer Predisposition Syndromes




Despite epidemiologic data supporting a significant genetic contribution to the cause of genitourinary malignancies, their diagnosis rarely results in clinical genetics referral and the heritability of prostate, bladder, kidney, and testicular cancer remains poorly understood. Little of this inheritance has been explained by rare, high-penetrance predisposition syndromes and, although rare genetic variation may explain some of the remaining familial predisposition, recent genome-wide association studies support an important causal role for more common genomic variation and other structural variants. Susceptibility loci associated with risk of prostate, bladder, and testicular cancer have been identified that may improve our understanding of the cause and natural history of these malignancies. It remains to be seen whether this emerging knowledge of genetic predisposition can meaningfully contribute to the clinical management of genitourinary malignancies.


Genitourinary malignancies comprise a heterogenous group of cancers of the prostate, bladder, kidney, and testis that either, only (prostate and testis), or, more commonly (bladder male/female ratio 3:1; kidney male/female ratio 2:1), occur in men. Early epidemiologic studies recognized a hereditary component to all 4 cancers, and subsequent linkage studies identified several rare syndromes whose phenotypes include a genitourinary malignancy ( Table 1 ). Among these 4 cancers, testicular cancer seems to have the highest familial clustering, followed by prostate, kidney, and then bladder cancer.



Table 1

Predisposition syndromes whose phenotype contains a genitourinary malignancy





































Cancer Predisposition Syndrome
Prostate HBOC
Urothelial Lynch
Hereditary RB
Costello
Apert
Testicular Peutz–Jeghers
Carney complex
Kidney Birt–Hogg–Dubé
HLRCC
Von Hippel–Lindau
HPRCC
WAGR
Tuberous sclerosis

Abbreviations: HBOC, hereditary breast-ovarian cancer; HLRCC, hereditary leiomyomatosis and renal cell cancer; HPRCC, hereditary papillary renal carcinoma; RB, retinoblastoma; WAGR, Wilms tumor-aniridia-genitourinary anomalies-mental retardation.


Prostate cancer is the most frequent nondermatologic malignancy in the United States and the second commonest cause of cancer death in men, after lung cancer. Despite evidence from segregation analyses supporting the existence of prostate cancer susceptibility genes, few have been identified. BRCA is a rare exception that has been consistently replicated and seems to explain 2% to 5% of familial prostate cancer ( Table 2 ). The discovery of germline determinants of bladder cancer has been similarly elusive. Familial bladder cancer is well recognized but its genetic cause has not yet been explained, and associations with rare predisposition syndromes such as Lynch syndrome (LS) or hereditary retinoblastoma (RB) explain only a minority of its inheritance. The incidence of renal cell cancer is increasing annually, largely because of the incidental discovery of small kidney tumors on imaging whose cause remains poorly understood. Birt-Hogg-Dubé (BHD) syndrome, hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC), von Hippel-Lindau (VHL) syndrome and Wilms tumor-aniridia-genitourinary anomalies-mental retardation (WAGR) explain some, but, again, a minority of hereditary kidney cancer. Testicular cancer is most common in white men with a 75% lower incidence reported in African American men, and, like kidney cancer, its incidence is increasing annually. The cause of this increased incidence is unknown, but sons and brothers of affected men have a six- to tenfold increased risk of developing testicular cancer, and family history is the strongest risk factor for the disease, suggesting a strong genetic component.



Table 2

Candidate genes for prostate, bladder, testicular, and bladder cancer predisposition



































































Cancer Candidate Genes
Prostate BRCA1 and 2
HPC1
PCAP
HPCX
CAPB
ELAC2/HPC2
HPC20
KLF6
AMACR
MSR1
NBS1
CHEK2
Urothelial MMR
RB
FGFR2
HRAS
NAT2
GSTM1
Testicular KITLG
SPRY4
PRKAR1A
STK11(LKB1)
Kidney FLCN
FH
MET
VHL
WT1
TSC


Prostate cancer


The Evidence for Hereditary Prostate Cancer


Prostate cancer is an umbrella term for a clinically heterogenous group of diseases with distinct natural histories. Despite strong evidence for the existence of prostate cancer susceptibility genes, family-based linkage studies have been unable to identify compelling candidates. This raises the possibility that the clinical heterogeneity may be further complicated by an underlying genetic heterogeneity that the studies performed to date have been underpowered to detect.


Age, ethnicity, and family history are the principal risk factors for prostate cancer. Family history has been confirmed as a risk factor for prostate cancer irrespective of age, race, or ethnicity, with a reported odds ratio of 2.5 (95% confidence interval [CI], 1.9–3.3) after adjusting for age and ethnicity. In Sweden, a population-based study suggested that approximately 11.6% of all prostate cancer can be accounted for by familial factors alone. A meta-analysis of 33 studies investigating familial clustering suggested that risk was greater for men with affected brothers (risk ratio [RR], 3.4; 95% CI, 1.8–5.7) than for men with affected fathers (RR, 2.2; 95% CI, 1.9–2.5), and risk increased with the number of close relatives affected. Second-degree relatives (RR, 1.7; 95% CI, 1.1–2.6) conferred a lower risk than first-degree relatives, and 2 or more first-degree relatives (RR, 5.1; 95% CI, 2.6–4.2) conferred increased risk compared with 1 (RR, 3.3; 95% CI, 2.6–4.2). Twin studies have further investigated this familial clustering and confirmed a strong genetic component, with a concordance among monozygotic twins of 27% compared with 7.1% between dizygotic twins, suggesting that 42% (CI, 29%–50%) of prostate cancer risk is caused by hereditary factors.


The incidence of prostate cancer is 24 to 60 times higher in Western compared with Asian countries, and in the United States, incidence rates are 60% higher for African American men than for whites. Although the availability of screening may bias ethnic variations in disease incidence, the magnitude of the difference supports the credibility of this association. Dissecting the interplay of genetic, environmental, and social factors that contribute to these differences is challenging, but would undoubtedly be helped by an improved understanding of the genetic factors involved.


The later median age of onset of prostate cancer may support a polygenic inheritance pattern. With increasing age, somatic mutations accumulate in cells. Many predisposition syndromes, for example hereditary breast-ovarian cancer syndrome caused by germline BRCA mutations, manifest clinically when a second mutation occurs in a specific gene (the Knudson 2-hit hypothesis). Affected individuals inherit 1 abnormal copy of the gene, but the second normal copy of the gene must be knocked out, so that gene function is lost and the disease phenotype develops. If prostate cancer inheritance followed a similar pattern, and several different genes had to be lost before disease occurred, this may explain why early-onset prostate cancer is unusual and why individuals with inherited predisposition still develop late-onset disease.


Many segregation studies have been performed in an effort to explain the pattern of prostate cancer inheritance. Data supporting autosomal recessive, X-linked, and multifactorial inheritance have been reported but the strongest evidence is for a rare autosomal dominantly inherited gene with an allele frequency of 0.3% to 1.7%. However, such a gene would only explain a minority of prostate cancer inheritance and it remains likely that many prostate cancer susceptibility genes exist.


Prostate Cancer Candidate Genes


BRCA-associated prostate cancer


Linkage studies of familial prostate cancer have identified many prostate cancer susceptibility loci, but few candidates have been replicated. Linkage studies have compared genomic markers between cases and controls with the hope of detecting links between regions of the genome and disease, and many factors contribute to the disappointing results thus far. The phenotypic variation of prostate cancer makes linkage analysis difficult. Even within families, clinical presentation varies and natural history differs, suggesting that relatives may develop genetically heterogenous disease. Because of the prevalence of the disease, some individuals (phenocopies) may develop sporadic prostate cancer that is different from the hereditary disease in the family. Prostate cancer screening may also detect individuals who may not otherwise be diagnosed, further complicating the study of inheritance within families. More recent efforts have attempted to study a clinically homogenous population to increase the likelihood of identifying underlying genes; however, the predictive power of clinical variables in prostate cancer is limited, and accurate clinical definition of prostate cancer continues to hamper linkage analysis. Molecular characterization of prostate cancer may facilitate more reliable disease classification and consequently aid the investigation of predisposition.


Although early studies of smaller subsets of patients were inconclusive, recent studies have associated BRCA1 and BRCA2 mutations with a hereditary predisposition to prostate cancer, noting up to a 33% cumulative risk by age 80 years. The evidence for BRCA2 is particularly compelling with a recent study in the United Kingdom attributing a 23-fold increase in risk of early-onset prostate cancer to BRCA2 mutations. The role of BRCA1 in hereditary prostate cancer is less clear. Linkage studies have identified the BRCA1 -containing region of chromosome 17q as a prostate cancer susceptibility region, but deleterious BRCA1 mutations have been inconsistently detected. Furthermore, a study investigating loss of heterozygosity in prostate cancer specimens from BRCA1 and BRCA2 carriers confirmed loss of heterozygosity in 10 of the 14 BRCA2 carriers but in none of the BRCA1 carriers, suggesting that germline BRCA1 mutations may not have played a role in prostate cancer pathogenesis in these individuals. It is possible that a prostate cancer susceptibility locus lies near (ie, is in linkage disequilibrium with) BRCA1 , explaining the positive linkage studies but failed confirmatory BRCA1 mutation testing.


The association between BRCA and prostate cancer exists in both multiethnic cohorts, such as the Breast Cancer Linkage Consortium study of hereditary breast-ovarian cancer kindreds, and in ethnic minorities such as men of Ashkenazi Jewish ancestry where founder mutation studies mirror the increased risk in broader population cohorts. A study of 5000 Ashkenazi Jewish participants in the United States reported that BRCA carriers had a cumulative risk for prostate cancer of 16% compared with 3.8% for noncarriers. This increased risk for male carriers was the same as the 16% absolute ovarian cancer risk for female BRCA carriers in the study. However, in men unselected for family history or ancestry, BRCA seems to contribute to a very small minority of prostate cancer risk, with a study of 290 men in the United States with early-onset prostate cancer reporting a BRCA2 prevalence rate of only 0.78% (2 mutation carriers). However, given the estimated 0.0069 BRCA2 mutation frequency in the population and the approximately threefold relative risk for prostate cancer, this translates to ˜1.5% of the 180,000 prostate cancer cases in the United States that are attributable to BRCA2 mutations, or 2790 cases each year that could benefit from treatments tailored to BRCA2 status.


Recent data suggest that BRCA -associated prostate cancer may represent an aggressive disease phenotype, and that carriers may require a unique management approach with earlier screening and more aggressive treatment. BRCA carriers seem to progress earlier and die more commonly of prostate cancer than noncarriers, supporting the need for more aggressive therapy. A recent phase I study demonstrated that prostate cancer responds to poly-ADP ribose polymerase inhibition offering a relatively nontoxic therapeutic option for a genetically defined subset of prostate cancer, and illustrating how germline variation may meaningfully contribute to prostate cancer management.


Other prostate cancer susceptibility loci


Few prostate cancer susceptibility loci have been as well studied as BRCA1 and BRCA2 , but many others have been identified. Initial studies in Polish patients associated germline mutations in another breast cancer susceptibility locus, CHEK2 , with prostate cancer, and reported that founder mutations explained up to 7% of prostate cancer in Poland. A subsequent study in Ashkenazi Jewish men with prostate cancer failed to replicate these findings, and this pattern has been repeated with many other candidate genes. A susceptibility locus at 1q24, termed HPC1 , was initially linked with prostate cancer in high-risk families, and deleterious mutations in a nearby gene RNASEL at 1q25 were believed to be responsible for this association. Numerous studies have attempted to verify this finding, with some confirming the initial reports and others refuting them, suggesting that, if the association is real, it likely explains a very small percentage of familial prostate cancer, and again highlighting the pattern in linkage studies to date.


Recent advances, such as the HapMap project and the emergence of high-throughput genotyping, have facilitated more detailed scrutiny of the genome, and 8 independent prostate cancer genome-wide association studies (GWAS) have identified further susceptibility loci. 8q24 is a region that contains no known genes (a gene desert) but has been consistently associated with prostate cancer in these studies, suggesting that it somehow plays a role in prostate cancer carcinogenesis. Recent evidence supports a possible role in regulation of the MYC proto-oncogene, which is found nearby. An association between prostate cancer and the 8q21 region was previously made through the Nijmegen Breakage syndrome, caused by NBS1 mutations. This a rare autosomal recessive condition characterized by short stature, progressive microcephaly with loss of cognitive skills, premature ovarian failure in women, recurrent sinopulmonary infections, and an increased risk lymphoma and leukemia. Adult heterozygotes have an increased risk of breast cancer, prostate cancer, and melanoma, contributing to a tiny proportion of overall cases because of the rarity of this syndrome, but supporting the association between this chromosomal region and malignancy.


Accumulating data from GWAS is providing evidence for a polygenic inheritance pattern in prostate cancer. Many independent loci have been replicated in different studies. A recent population-based, case-control study from Sweden concluded that the population attributable risk (PAR) of a susceptibility single nucleotide polymorphism (SNP) panel was 4% to 21%, depending on the number of SNPs detected, and, when family history was added into the model, the PAR was 46%. Available technology detects approximately 80% of common variation in the genome. This detection rate will improve, enabling more detailed scanning and further susceptibility loci will be identified. Explanation of prostate cancer inheritance will likely require an improved understanding of the interaction between these distinct genomic regions. The contribution of DNA structural variants (eg, copy number variation, microRNAs, long-range promoters, and epigenetics) to gene expression is being investigated and may also improve understanding of hereditary and familial prostate cancer.


Summary of Prostate Cancer Predisposition


Phenotypic variation and genetic heterogeneity have complicated the search for prostate cancer susceptibility genes. Many candidates have been identified but few results have been consistently replicated. BRCA2 is one exception that has repeatedly been associated with prostate cancer, and, more recently, with an aggressive subset of the disease, but accounts for a small percentage (<1%) of overall prostate cancer susceptibility. Recent GWAS have identified common variants associated with prostate cancer and, as this technology advances and our understanding of the genome improves, the role these loci play in prostate cancer susceptibility may emerge. It remains possible that rare, single-gene disorders explain familial predisposition to cancer, but more accurate clinical and/or molecular characterization of disease within families will be required to utilize recent technological advances and to identify these genes.




Bladder cancer


The Evidence for Hereditary Bladder Cancer


Bladder cancer is the fifth commonest malignancy in the United States and, because of the cost of screening, is the most expensive to manage, making it an important public health issue. Transitional cell carcinoma represents more than 90% of bladder cancer. It most commonly occurs in the bladder but also arises in the renal pelvis or ureter (upper urinary tract), and, irrespective of its site of origin, is collectively termed urothelial cancer (UC). Many environmental causes of UC have been reported, among them smoking and exposure to aromatic amines, but epidemiologic data suggest that poorly defined genetic factors also play a role.


A population-based study in Utah reported that first-degree relatives of individuals with bladder cancer have an increased risk (RR, 1.51; 95% CI, 0.98–2.2) of developing the disease, and this increased to 5.07 (95% CI, 0.97–12.5) when the proband was less than 60 years of age. There are 16 multiple-case UC reports in the literature, detailing 32 families with 86 affected individuals. The early age of onset and co-occurrence of other malignancies seems to suggest a genetic predisposition, but it is difficult to separate this from shared environmental exposure. A large Dutch case-control study of 1193 UC cases and 853 controls reported a smoking-adjusted relative risk of 1.8 (95% CI, 1.3–2.7) for a positive family history of UC, suggesting that smoking history and genetic susceptibility are independent risk factors for the disease. Other case-control and cohort studies completed to date support a modest hereditary component to UC, with most risk ratios lying between 1.4 and 1.9.


High-penetrance UC Genes


The most common hereditary cancer syndrome with UC as a characteristic is LS. This is an autosomal dominantly inherited condition resulting from germline mutation in mismatch repair (MMR) genes. It is the most common form of hereditary colorectal cancer and extracolonic manifestations include many malignancies, including UC. The revised Bethesda Guidelines, which were developed to help identify individuals and families who may be at risk for LS, include UC of the upper tract but not bladder among the syndrome-defining malignancies. Although several reports of bladder cancer in LS exist, the association remains unclear. A Dutch LS study reported an RR of 14 (95% CI, 6.7–29.5) for upper-tract UC, but the risk for developing UC of the bladder was not increased in this cohort. A discussion of screening for UC is beyond the scope of this manuscript, but guidelines for individuals with UC presently recommend considering annual urinary cytology.


UC has been reported as a manifestation of other rare, high-penetrance syndromes. An association with hereditary RB was initially believed to be related to treatment effects from primary therapy for the RB ; however, survivors who did not receive radiation or chemotherapy had a considerably higher bladder cancer–specific mortality (standardized mortality ratio, 26.3; 95% CI, 8.5–61.4) than is seen in the general population, suggesting that UC of the bladder is a manifestation of hereditary RB. This is consistent with data demonstrating somatic mutations in RB or p53 in 50% of high-grade UC. Somatic mutations in HRAS and FGFR3 are commonly found in superficial UC. Costello syndrome is a hereditary condition with a large number of characteristic features, including UC of the bladder for adolescents and adults. HRAS is the only known mutation associated with this syndrome and, again, this germline association is consistent with somatic alterations identified in superficial UC. Germline FGFR3 mutations cause achondroplasia that is not associated with an increased risk of UC, but Apert syndrome, which results from mutations in FGFR2, has been associated with UC.


These high-penetrance predisposition syndromes explain a small minority of familial UC. Linkage studies have failed to identify other genes, and, although they have been small and underpowered, they seem to suggest a polygenic inheritance for the familial UC.


Low-penetrance UC Genes


Two candidate genes involved in carcinogen metabolism have been associated with an increased risk of bladder cancer. N -acetyltransferase 2 ( NAT2 ) is a phase II enzyme that detoxifies aromatic amines, 1 family of carcinogens found in tobacco smoke, and glutathione S-transferase ( GSTM1 ) is a phase II enzyme that detoxifies carcinogenic polycyclic aromatic hydrocarbons, such as benzopyrene. The NAT2 slow acetylator phenotype and the GSTM1 null genotype increase bladder cancer risk by 1.4- and 1.5-fold respectively, but, because of their high prevalence in the white population (40%–60% and 40%–50% of whites respectively), have been estimated to account for 31% of bladder cancer in whites.


Further support for the role of common genomic variation in bladder cancer predisposition was provided by recent GWAS. In a study of 4000 cases and 38,000 controls, Kiemeney and colleagues identified 3 new susceptibility loci at 8q24, 3q28, and 5p15 that increase the risk of bladder cancer by 22%, 19%, and 16%, respectively. The same 8q24 locus has been associated with prostate cancer as discussed earlier, as well as colorectal and breast cancer, suggesting that this poorly understood region may contain a common carcinogenic pathway. A second GWAS in 969 bladder cancer cases and 957 controls identified a second, independent SNP on 8q24 located in the promoter region of PSCA.


Summary of Bladder Cancer Predisposition


Individuals with LS are screened for UC, but most familial UC remains unexplained. Candidate genes involved in carcinogen metabolism have been associated with increased risk of the disease, and recent GWAS have identified further common variants that confer increased risk of UC. Like prostate cancer, UC seems to be a polygenic disorder, although rare familial single-gene disorders may exist. More is known about environmental causes of bladder cancer than the other genitourinary malignancies discussed, and future studies investigating genetic susceptibility should consider gene-environment interaction in the analysis.




Bladder cancer


The Evidence for Hereditary Bladder Cancer


Bladder cancer is the fifth commonest malignancy in the United States and, because of the cost of screening, is the most expensive to manage, making it an important public health issue. Transitional cell carcinoma represents more than 90% of bladder cancer. It most commonly occurs in the bladder but also arises in the renal pelvis or ureter (upper urinary tract), and, irrespective of its site of origin, is collectively termed urothelial cancer (UC). Many environmental causes of UC have been reported, among them smoking and exposure to aromatic amines, but epidemiologic data suggest that poorly defined genetic factors also play a role.


A population-based study in Utah reported that first-degree relatives of individuals with bladder cancer have an increased risk (RR, 1.51; 95% CI, 0.98–2.2) of developing the disease, and this increased to 5.07 (95% CI, 0.97–12.5) when the proband was less than 60 years of age. There are 16 multiple-case UC reports in the literature, detailing 32 families with 86 affected individuals. The early age of onset and co-occurrence of other malignancies seems to suggest a genetic predisposition, but it is difficult to separate this from shared environmental exposure. A large Dutch case-control study of 1193 UC cases and 853 controls reported a smoking-adjusted relative risk of 1.8 (95% CI, 1.3–2.7) for a positive family history of UC, suggesting that smoking history and genetic susceptibility are independent risk factors for the disease. Other case-control and cohort studies completed to date support a modest hereditary component to UC, with most risk ratios lying between 1.4 and 1.9.


High-penetrance UC Genes


The most common hereditary cancer syndrome with UC as a characteristic is LS. This is an autosomal dominantly inherited condition resulting from germline mutation in mismatch repair (MMR) genes. It is the most common form of hereditary colorectal cancer and extracolonic manifestations include many malignancies, including UC. The revised Bethesda Guidelines, which were developed to help identify individuals and families who may be at risk for LS, include UC of the upper tract but not bladder among the syndrome-defining malignancies. Although several reports of bladder cancer in LS exist, the association remains unclear. A Dutch LS study reported an RR of 14 (95% CI, 6.7–29.5) for upper-tract UC, but the risk for developing UC of the bladder was not increased in this cohort. A discussion of screening for UC is beyond the scope of this manuscript, but guidelines for individuals with UC presently recommend considering annual urinary cytology.


UC has been reported as a manifestation of other rare, high-penetrance syndromes. An association with hereditary RB was initially believed to be related to treatment effects from primary therapy for the RB ; however, survivors who did not receive radiation or chemotherapy had a considerably higher bladder cancer–specific mortality (standardized mortality ratio, 26.3; 95% CI, 8.5–61.4) than is seen in the general population, suggesting that UC of the bladder is a manifestation of hereditary RB. This is consistent with data demonstrating somatic mutations in RB or p53 in 50% of high-grade UC. Somatic mutations in HRAS and FGFR3 are commonly found in superficial UC. Costello syndrome is a hereditary condition with a large number of characteristic features, including UC of the bladder for adolescents and adults. HRAS is the only known mutation associated with this syndrome and, again, this germline association is consistent with somatic alterations identified in superficial UC. Germline FGFR3 mutations cause achondroplasia that is not associated with an increased risk of UC, but Apert syndrome, which results from mutations in FGFR2, has been associated with UC.


These high-penetrance predisposition syndromes explain a small minority of familial UC. Linkage studies have failed to identify other genes, and, although they have been small and underpowered, they seem to suggest a polygenic inheritance for the familial UC.


Low-penetrance UC Genes


Two candidate genes involved in carcinogen metabolism have been associated with an increased risk of bladder cancer. N -acetyltransferase 2 ( NAT2 ) is a phase II enzyme that detoxifies aromatic amines, 1 family of carcinogens found in tobacco smoke, and glutathione S-transferase ( GSTM1 ) is a phase II enzyme that detoxifies carcinogenic polycyclic aromatic hydrocarbons, such as benzopyrene. The NAT2 slow acetylator phenotype and the GSTM1 null genotype increase bladder cancer risk by 1.4- and 1.5-fold respectively, but, because of their high prevalence in the white population (40%–60% and 40%–50% of whites respectively), have been estimated to account for 31% of bladder cancer in whites.


Further support for the role of common genomic variation in bladder cancer predisposition was provided by recent GWAS. In a study of 4000 cases and 38,000 controls, Kiemeney and colleagues identified 3 new susceptibility loci at 8q24, 3q28, and 5p15 that increase the risk of bladder cancer by 22%, 19%, and 16%, respectively. The same 8q24 locus has been associated with prostate cancer as discussed earlier, as well as colorectal and breast cancer, suggesting that this poorly understood region may contain a common carcinogenic pathway. A second GWAS in 969 bladder cancer cases and 957 controls identified a second, independent SNP on 8q24 located in the promoter region of PSCA.


Summary of Bladder Cancer Predisposition


Individuals with LS are screened for UC, but most familial UC remains unexplained. Candidate genes involved in carcinogen metabolism have been associated with increased risk of the disease, and recent GWAS have identified further common variants that confer increased risk of UC. Like prostate cancer, UC seems to be a polygenic disorder, although rare familial single-gene disorders may exist. More is known about environmental causes of bladder cancer than the other genitourinary malignancies discussed, and future studies investigating genetic susceptibility should consider gene-environment interaction in the analysis.




Kidney cancer


Hereditary Kidney Cancer Syndromes


Conservative estimates suggest that 3% to 5% of kidney tumors are inherited. Explanation of the genetic causes of hereditary renal cancer (HRC) identified important molecular pathways in renal cell cancer pathogenesis. This understanding has proved instrumental in the development of clinical trials with targeted molecular therapies, which have become the new standards for medical therapies. Several HRC syndromes have been characterized. These include VHL disease, BHD syndrome, hereditary papillary (type I) renal cancer (HPRC), HLRCC, and tuberous sclerosis (TS) ( Table 3 ). Others, including familial renal oncocytoma and the association between lymphoma and kidney cancer, have been reported, although genetic evidence is lacking.



Table 3

Biologic basis of hereditary renal tumor syndromes








































Syndrome Gene/Protein Function Pathway a Phenotype
VHL 3p25/pVHL TS HIF CNS/ocular hemangioblastoma
ELST
Pheochromocytoma
Pancreatic NET
Clear cell RCC
HPRC 7q31/c-Met Tyrosine kinase domain OG HGF/c-Met Papillary type 1 RCC
BHD 17p12/folliculin TS mTOR Fibrofolliculomas
Pulmonary blebs
Chromo/onco/clear RCC
HLRCC 1q42.3/fumarase TS HIF Skin leiomyoma
Uterine Leiomyoma/sarcoma
HLRCC renal cancer
TSC TSC1 9q34
TSC2 16p13.3 tubulin/hamartin
TS mTOR Angiomyolipoma
Clear cell RCC

Abbreviations: BHD, Birt-Hogg-Dubé; Chromo, chromophobe; CNS, central nervous system; ELST, endolymphatic sac tumors; HGF, hepatocyte growth factor; HIF, hypoxia inducible factor; HLRCC, hereditary leiomyomatosis renal cell carcinoma; HPRC, hereditary papillary renal cancer; mTOR, mammalian target of rapamycin; NET, neuroendocrine tumors; OG, oncogene; Onco, oncocytoma; RCC, renal cell carcinoma; TS, tumor suppressor; TSC, tuberous sclerosis complex; VHL, von Hippel-Lindau.

a Putative primary pathway for mechanism of action.



VHL disease


The VHL syndrome first reported in 1895 by a German ophthalmologist, Dr Eugene von Hippel, and fully described by Davison and colleagues in 1936, includes brain and retinal hemangioblastomas, endolymphatic sac tumors of the ear, clear cell renal cancer and renal cysts, pheochromocytoma, pancreatic neuroendocrine tumors and cysts, as well as cysts in the epididymis of the testis in men and of the broad ligament in women.


The VHL gene has been localized on the short arm of chromosome 3 (3p26–25) and functions as a classic tumor suppressor gene. VHL syndrome is present in an estimated 1 in 36,000 individuals, and germline mutations are inherited in an autosomal dominant fashion. The VHL gene functions as part of a complex with other proteins that regulate hypoxia inducible factor (HIF)-1α and HIF-2α. Mutations which result in the inactivation of VHL, either directly or through epigenetic events such as methylation, allow for unregulated action of HIF even in conditions of normoxia. Aberrant activation of HIF-dependent pathways creates a condition of pseudohypoxia believed to provide the environment for neovascularization and cellular proliferation associated with renal cell carcinoma.


Four distinct VHL phenotypes have been described ( Table 4 ). Type 1 families do not have pheochromocytomas. Those with type 2 may have pheochromocytoma found among family members and are further subdivided into 2a (low risk for renal cancer), 2b (high risk for renal cancer), and 2c (pheochromocytoma only). Earliest manifestations of the disease are detectable among most affected individuals within the first 25 years of life. Central nervous system (CNS) and ocular hemangiomas may be detected in children and infants. The most common current cause of morbidity is from CNS hemangiomas, although, historically, complications of medical renal disease and kidney cancer have also been a major health risk. The renal manifestations of VHL are found in approximately 40% to 50% of patients, and vary from cystic to solid lesions, typically multifocal and bilateral. Organ-preserving approaches for control of VHL neoplasms are considered standard treatment and should be used when possible.



Table 4

Clustered phenotypes of VHL (based on the presence of pheochromocytomas and renal tumors)






















VHL Group Phenotype
Type 1 Low risk of pheochromocytoma
Type 2 High risk of pheochromocytoma
2a Hemangiomas, low-risk RCC
2b Hemangiomas, high-risk RCC
2c Pheochromocytoma predominant


HPRC


HPRC is associated with mutation of the c-met oncogene. C-met has been mapped to the long arm of chromosome 7 (7q31) and codes for a membrane-bound tyrosine kinase receptor whose ligand is hepatocyte growth factor (HGF). In HPRC, kidney tumors are formed as a result of activating mutations, typically involving the intracellular domain of the c-met receptor, causing constitutive activation of the HGF/c-met pathway through its function as a tyrosine kinase. Germline allelic imbalance through gains in chromosomes 7 and 17 has also been reported. Analysis of families with identifiable germline mutations has revealed an autosomal dominant inheritance pattern with variable penetrance.


The clinical manifestations of HPRC, unlike the multiorgan involvement seen in VHL, seem isolated to papillary renal tumors only. Screening studies in affected families have helped to describe details of the disease’ natural history. The median age for clinical presentation with tumors is in the fourth to fifth decade of life; older than that seen for VHL. Screening among families can be successful in detecting subclinical tumors earlier and can indicate a high degree of penetrance, with several hundred micropapillary tumors often present in resected kidneys.


Management of patients with HPRC must strike a balance between the risks of intervention and those of distant disease progression. Nephron-sparing surgery is the preferred approach, but, because of the number of gross and macroscopic tumors encountered, repeated interventions are often necessary. Clinical trials investigating inhibitors of c-met are underway.


BHD syndrome


BHD syndrome is characterized by skin fibrofolliculomas, pulmonary cysts, and renal tumors. Several series evaluating familial disease clusters have identified variable penetrance patterns and phenotypes. The largest series reported a 14% prevalence of renal tumors in mutation carriers. Spontaneous pneumothoraces occurred in 23% of affected individuals and were most common in younger family members (<40 years old). Lung cysts were common and seen in 83% of screened patients as detected on high-resolution chest computed tomography (CT). A more recent study that screened 50 newly diagnosed families identified skin lesions in 90% of affected individuals and renal tumors in 34%.


Variable renal manifestations have been described, including chromophobe, oncocytoma, clear cell, and hybrid oncocytic tumors composed of elements of oncocytoma and chromophobe, and the average age of presentation is between 40 and 50 years. In the largest pathologic series to date, consisting of 130 tumors from 30 surgically managed patients, the distribution of renal tumor histopathology was as follows: hybrid onco/chromophobe 50%, chromophobe 34%, conventional clear cell 9%, oncocytoma 5%, and papillary 2%. Other possibly related manifestations include multinodular goiter, medullary thyroid carcinoma, parotid oncocytoma, and colonic polyposis.


BHD is an autosomal dominant condition caused by mutations in the folliculin, and has been mapped to chromosome 17 (17p12q11). Folliculin has no known function but has been isolated in brain, parotid gland, lung, pancreas, breast, prostate, kidney, and skin. It may play a role in the mTOR pathway, mediated though binding of the folliculin-interacting protein and the 5′-activated protein kinase.


HLRCC


HLRCC is associated with a more malignant type II variant of papillary renal cancer. HLRCC is an autosomal dominant condition caused by germline mutations of fumarate hydratase (FH), a Krebs cycle enzyme. Detailed histologic descriptions facilitate identification of HLRCC renal tumors. Symptomatic uterine fibroids are the commonest clinical presentation, often requiring early hysterectomy because of difficulties from menometrorrhagia. In a recently described series in the United States, as many as 89% of affected women underwent hysterectomy, 44% before the age of 30 years. Isolated cases of uterine leiomyosarcomas have been reported, and biallelic mutations in nonsyndromic leiomyomas have been described. Cutaneous leiomyomas are common among affected individuals.


FH is located on chromosome 1 (1q42.3–43) and loss of heterozygosity studies support its role as a tumor suppressor gene. A genetic founder effect has been described for seemingly unrelated patients with similar clinicopathologic features. Initial descriptions of the syndrome focused entirely on the uterine abnormalities and dermatologic manifestations, referring to the syndrome as multiple cutaneous and uterine leiomyomatosis or multiple leiomyomatosis. Renal cortical tumors are typically found in 2% to 21% of affected individuals. The discrepancy between expressions of these 2 phenotypic findings has prompted some investigators to subclassify the disease based on phenotype. Biallelic loss of FH in several published models indicates that aberrant signaling may be mediated through HIF-dependent pathways, suggesting that mechanisms of pseudohypoxia or apoptosis may play roles in tumorigenesis similar to VHL. Reports of clear cell histology with FH mutation in a patient with HLRCC may support a common mechanism of tumorigenesis through HIF activation.


Management Summary for HRCs


A therapeutic and preventive strategy in patients with HRC requires coordinated multimodality care, which serves to minimize treatment related morbidity and preserve renal function. The general approach to HRC includes screening tests and physical examinations, as well as a regimented schedule of follow-up appointments. Recent advances in nephron-sparing techniques that prioritize functional kidney preservation and expectant management of lesions have diminished kidney-related mortality and chronic renal dysfunction. Retrospective studies have demonstrated the safety of observation of solid renal masses to a diameter of 3 cm. Minimally invasive surgical procedures for multiple partial nephrectomies have also been used satisfactorily at experienced centers, including tumor ablation performed in prospective clinical trials. Long-term outcomes with regard to efficacy and renal function have not been reported.


Syndrome-specific management strategies have also been developed. VHL mutation carriers require neurologic, otologic, ophthalmologic, and endocrine follow-up involving magnetic resonance imaging (MRI)/CT scanning. The development of pheochromocytomas can complicate patient management, increasing the risk of intracranial bleeding in patients at risk for CNS or ocular hemangiomas. Annual functional adrenal studies, and secondary meta-iodobenzylguanidine immunoscintigraphy are often indicated. Medical management before surgical resection is the most frequent management strategy. Partial adrenalectomy for a solitary adrenal gland or bilateral lesions can be safely performed to avoid steroid replacement therapy.


HLRCC management differs from other HRC syndromes because of the aggressive nature of renal tumors. Among affected individuals, rapid distant disease progression, even when the primary tumors are small, is usually the case. This is also evident in pediatric patients. As a result, thorough and early imaging assessment, close follow-up, and rapid intervention is the management paradigm for these patients. Nephron-sparing surgery is less well established in this setting, and complete wide excision, including lymph node dissection, should be attempted. Preoperative positron emission tomography scans may prove beneficial in cases where lymph node or nonlocalized disease is suspected.

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Mar 1, 2017 | Posted by in HEMATOLOGY | Comments Off on Genitourinary Cancer Predisposition Syndromes

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