Contents
Tuberous
Sclerosis and Other Inherited Renal Cancer Syndromes: Lessons from the Eker Rat
Executive Editors: Laura S. Schmidt / Okio Hino
Lessons from the Eker Rat Model: From Cage to
Bedside Pp.799-806
Raymond S. Yeung
Multistep Renal Carcinogenesis in the Eker (Tsc
2 Gene Mutant) Rat Model Pp.807-811
Okio Hino
The Eker Rat: Establishing a Genetic Paradigm
Linking Renal Cell Carcinoma and Uterine Leiomyoma Pp.813-824
J.D. Cook and C.L.
Walker
The Genetic Basis of Kidney Cancer: Why is
Tuberous Sclerosis Complex Often Overlooked? Pp.825-831
Elizabeth Petri Henske
Von Hippel-Lindau Disease Pp.833-842
Eamonn R. Maher
Familial Non-Syndromic Clear Cell Renal Cell
Carcinoma Pp.843-848
Emma R. Woodward
Chromosome 3 Translocations and Familial
Renal Cell Cancer Pp.849-854
Anita C.M. Bonne,
Danielle Bodmer, Eric F.P.M. Schoenmakers, Conny M. van Ravenswaaij, Nicoline
Hoogerbrugge and Ad Geurts van Kessel
Hereditary Papillary Renal Carcinoma Type I Pp.855-868
Pathirage G.
Dharmawardana, Alessio Giubellino and Donald P. Bottaro
Hereditary Leiomyomatosis and Renal Cell
Cancer (HLRCC) Pp.869-875
Maija Kiuru and Virpi
Launonen
Birt-Hogg-Dube Syndrome, a Genodermatosis
that Increases Risk for Renal Carcinoma Pp.877-885
Laura S. Schmidt
Natural History of the Nihon Rat Model of BHD
Pp.887-893
Kazuo Okimoto, Mami Kouchi,
Izumi Matsumoto, Junko Sakurai, Toshiyuki Kobayashi and Okio Hino
Renal Neoplasia in the Hyperparathyroidism-Jaw
Tumor Syndrome Pp.895-897
M.H. Tan and B.T. Teh
Abstracts
[Back to top] Lessons
from the Eker Rat Model: From Cage to Bedside
Raymond S. Yeung
Rodent models of human diseases serve a vital
role in translating bench observations to bedside therapies. In vivo
manipulation of these animals allows us to explore the biologic significance of
the underlying molecular and biochemical pathways. The study of human cancers
has been highly enriched by the observations made from numerous transgenic
mouse models. Long before the techniques of genetic engineering were
discovered, Dr. Reidar Eker described one of the earliest examples of an
autosomal dominant model of renal tumors in a unique strain of rats. They were
used in the 1980’s by Alfred Knudson to validate the “two-hit” hypothesis and
to study the multi-step process of carcinogenesis. Following the identification
of the Tsc2 germline mutation in the Eker rat, it became the first rodent model
of tuberous sclerosis and has since been exploited in many areas of tumor
biology as illustrated in the content of this issue. The focus of our review is
to highlight the contribution of the Eker rat towards understanding the Tsc2
signaling pathways in tumorigenesis and evaluating potential therapeutics in
the pre-clinical setting.
[Back to top] Multistep Renal
Carcinogenesis in the Eker (Tsc 2 Gene Mutant) Rat Model
Okio Hino
Cancer is a heritable disorder of somatic
cells. Environment and heredity both contribute to the origin of human cancer.
The Eker (Tsc 2 gene mutant) rat model of hereditary renal carcinoma
(RC) is an example of a Mendelian dominantly inherited predisposition to a
specific cancer in an experimental animal. To the best of our knowledge, this
was the first isolation of a Mendelian dominantly predisposing cancer gene in a
naturally occurring animal model. Carcinogenesis looks like an opened Japanese
fan, because initiated cells growing in several directions will develop into
tumors having many gene abnormalities, and this is suggested by the edge of the
fan. To search for such genetic alterations, we identified genes (Niban
and Erc) that were expressed more abundantly in renal tumors than in the
normal kidney.I will review this unique model for the study of multistep renal
carcinogenesis and discuss cancer prevention and delay of carcinogenesis.
[Back to top]
The Eker
Rat: Establishing a Genetic Paradigm Linking Renal Cell Carcinoma and Uterine
Leiomyoma
J.D. Cook and C.L.
Walker
Renal Cell Carcinoma (RCC) and uterine
leiomyoma (often referred to as fibroids) are tumors arising from tubular
epithelium and myometrial compartments of the kidney and uterus, respectively.
These tumors have a very different clinical presentation, with RCC being one of
the less common cancers, having a very poor prognosis, and occurring
predominantly in men, whereas uterine leiomyoma are the most common tumor of
women and are benign. Although they are distinct histologically, with RCC
arising from epithelial cells and leiomyoma arising from smooth muscle cells,
they share a common embryological origin. Renal tubular epithelial cells arise
during nephrogenesis as a result of the mesenchymal-epithelial transition of
condensed mesenchyme induced by the developing ureteric bud, and have a shared
mesenchymal lineage with smooth muscle cells of the uterus. In addition to a
common embryological origin, RCC and leiomyoma have been demonstrated to share
a common genetic etiology. The Eker rat model was the first demonstration of a
specific genetic linkage between RCC and uterine leiomyoma. Eker rats carry a
germline defect in the rat homologue of the tuberous sclerosis complex 2
(TSC-2) tumor suppressor gene and develop spontaneous RCC and uterine leiomyoma
with a high frequency. TSC patients are also at risk for RCC, and sporadic
human uterine leiomyomas exhibit loss of function of the TSC-2 gene product,
tuberin. Individuals with the inherited cancer syndrome hereditary
leiomyomatosis and renal cell cancer (HLRCC) that have germline defects in the
fumarate hydratase (FH) gene develop papillary RCC and uterine and skin
leiomyomas. Benign cutaneous lesions and uterine leiomyoma also arise in German
Shepherd dogs with germline mutations in the Birt-Hogg-Dube (BHD) gene, and
these animals develop RCC and uterine leiomyoma with a high frequency.
Identification of the tumor suppressor genes involved in these diseases, TSC,
FH and BHD, and the elucidation of the function of their protein products,
tuberin, fumarate hydratase and folliculin, respectively, opens new avenues for
understanding the pathogenesis of both RCC and uterine leiomyoma.
[Back to top]
The Genetic Basis
of Kidney Cancer: Why is Tuberous Sclerosis Complex Often Overlooked?
Elizabeth Petri Henske
Fifty years ago, the Eker rat was identified
as the first animal model of hereditary renal adenoma and carcinoma [1], with
histopathology resembling human renal carcinoma [2]. Ten years ago, a mutation
in the TSC2 gene was identified in the Eker rat at Fox Chase Cancer
Center by Yeung and Knudson [3], and in Tokyo by Kobayashi and Hino [4]. The
literature contains dozens of reports of renal cell carcinoma (RCC) in tuberous
sclerosis complex (TSC) patients, including tumors in children as young as five
and one report in an infant. Despite these facts, the association between TSC
and RCC is under-recognized, and sometimes completely omitted from discussions
of inherited renal carcinoma. Here, we will review the clinical association of
RCC in TSC, consider the factors that have led to its under-emphasis within the
RCC field, address the cellular and biochemical mechanisms that may contribute
to RCC in cells with TSC1 or TSC2 mutations, and finally discuss
the ways in which the TSC signaling pathways may be linked to sporadic RCC in
the general population.
[Back to top]
Von Hippel-Lindau
Disease
Eamonn R. Maher
Germline mutations in the VHL tumour
suppressor gene may cause a variety of phenotypes including von Hippel-Lindau
(VHL) disease, familial phaeochromocytoma and inherited polycythaemia. VHL
disease is a multisystem familial cancer syndrome and is the commonest cause of
familial renal cell carcinoma (RCC). VHL disease provides a paradigm for
illustrating how studies of a rare familial cancer syndrome can produce
advances in clinical medicin and important insights into basic biological
processes. Thus the identification of the VHL gene has improved the
diagnosis and clinical management of VHL disease and provided insights
into the pathogenesis of sporadic clear cell RCC. Functional investigations of
the VHL gene product have provided novel information on how cells sense
oxygen and the role of hypoxia-response pathways in human tumourigenesis. Such
information offers prospects of novel therapeutic interventions for VHL
disease and common cancers including RCC.
[Back to top]
Familial
Non-Syndromic Clear Cell Renal Cell Carcinoma
Emma R. Woodward
The diagnosis of familial non-syndromic clear
cell renal cell carcinoma is one of exclusion. In families presenting with
clear cell RCC a germline VHL mutation and a consitutional translocation
of chromosome 3 must be excluded before familial non-syndromic clear cell RCC
can be diagnosed. Large familial non-syndromic clear cell RCC kindreds are
uncommon and a predisposing gene has not been identified. However inheritance
is autosomal dominant in most cases and age at onset is earlier than in
sporadic cases. Recognition and appropriate screening of familial non-syndromic
clear cell RCC cases will reduce morbidity and mortality. Large scale collaborative
linkage studies may provide a basis for the identification of familial
non-syndromic clear cell RCC susceptibility gene(s).
[Back to top] Chromosome 3 Translocations and Familial
Renal Cell Cancer
Anita C.M. Bonne,
Danielle Bodmer, Eric F.P.M. Schoenmakers, Conny M. van Ravenswaaij, Nicoline
Hoogerbrugge and Ad Geurts van Kessel
Renal cell carcinomas (RCCs) occur in both sporadic
and familial forms. In a subset of families the occurrence of RCCs
co-segregates with the presence of constitutional chromosome 3 translocations.
Previously, such co-segregation phenomena have been widely employed to identify
candidate genes in various hereditary (cancer) syndromes. Here we survey the
translocation 3- positive RCC families that have been reported to date and the
subsequent identification of its respective candidate genes using positional
cloning strategies. Based on allele segregation, loss of heterozygosity and
mutation analyses of the tumors, a multi-step model for familial RCC
development has been generated. This model is relevant for (i) understanding
familial tumorigenesis and (ii) rational patient management. In addition, a high
throughput microarray-based strategy is presented that will enable the rapid
identification of novel positional candidate genes via a single step procedure.
The functional consequences of the (fusion) genes that have been identified so
far, the multi-step model and its consequences for clinical diagnosis, the
identification of persons at risk and genetic counseling in RCC families are
discussed.
[Back to top] Hereditary Papillary Renal Carcinoma Type I
Pathirage G.
Dharmawardana, Alessio Giubellino and Donald P. Bottaro
Germline missense mutations in the tyrosine
kinase domain of the hepatocyte growth factor/scatter factor (HGF/SF) receptor,
c-Met, are thought to be responsible for hereditary papillary renal carcinoma
(HPRC) type 1, a form of human kidney cancer. In addition to extensive linkage
analysis of HPRC families localizing the HPRC type 1 gene within chromosome 7,
the demonstration that individual c-Met mutations reconstituted in cultured
cells display enhanced and dysregulated kinase activity, and confer cell
transformation and tumorigenicity in mice, solidifies this conclusion. Our
prior knowledge of HGF/SF biology and c-Met signaling enabled rapid progress in
unraveling the molecular pathogenesis of HPRC type 1, and in laying the
framework for the development of novel therapeutics for the treatment of this
cancer. At the same time, the study of HPRC type 1 has refined our appreciation
of the oncogenic potential of c-Met signaling, and challenges our current
understanding of HGF/SF and c-Met function in health and disease.
[Back to top]
Hereditary Leiomyomatosis and
Renal Cell Cancer (HLRCC)
Maija Kiuru and Virpi
Launonen
Hereditary leiomyomatosis and renal cell
cancer (HLRCC) (MIM 605839) is a recently identified autosomal dominant tumor
susceptibility syndrome characterized by predisposition to benign leiomyomas of
the skin and the uterus (fibroids, myomas). Susceptibility to early-onset renal
cell carcinoma and uterine leiomyosarcoma is present in a subset of families.
Renal cell carcinomas are typically solitary and aggressive tumors displaying
papillary type 2 or collecting duct histology. The disease predisposing gene
was identified as fumarate hydratase (fumarase, FH) (MIM
136850). FH encodes an enzyme that operates in the mitochondrial Krebs
cycle being thus involved in cellular energy metabolism. The recent discovery
of HLRCC and the predisposing gene FH has increased the present
knowledge of hereditary renal cancer and enabled identification of the
predisposed individuals. This review provides the present knowledge of the
clinical, histopathological, and molecular features of HLRCC. Future prospects related
to studies on the phenotype and molecular biology of HLRCC will also be
discussed.
[Back to top] Birt-Hogg-Dube Syndrome, a Genodermatosis
that Increases Risk for Renal Carcinoma
Laura S. Schmidt
Over the past decade cancer-causing genes
have been identified for the most common histologic types of renal cancer,
specifically clear cell, papillary type 1 and papillary type 2. Genes
predisposing to the more rare chromophobe renal carcinoma and renal oncocytoma
were unknown until the recent discovery of a novel gene, BHD, on
chromosome 17p that was found to be mutated in the germline of affected family
members with the Birt-Hogg-Dubé (BHD) syndrome. These patients develop the
hallmark BHD skin lesions (fibrofolliculomas), lung cysts and spontaneous
pneumothorax. Importantly, BHD patients have an increased risk for developing a
variety of renal neoplasia, most commonly chromophobe and oncocytic hybrid
tumors. This review will describe the phenotypic manifestations of BHD
including the histologic features of BHD-associated renal tumors, the
identification of this novel renal cancer-predisposing gene, the BHD mutation
spectrum found in BHD patients, and will discuss the potential role of BHD
as a tumor suppressor gene.
[Back to top] Natural History of the Nihon Rat Model of BHD
Kazuo Okimoto, Mami Kouchi, Izumi Matsumoto, Junko Sakurai, Toshiyuki Kobayashi and Okio Hino
Hereditary cancer was first described in the
rat by Eker and Mossige in 1954 in Oslo. The Eker rat model of hereditary renal
carcinoma (RC) was the first example of a Mendelian dominantly inherited
predisposition to a specific cancer in an experimental animal, and has been
contributing to the elucidation of renal carcinogenesis. Recently, we found a
second hereditary RC model in the Sprague-Dawley (SD) rat, in Japan in 2000,
which was named the Nihon rat. The Nihon rat is also an example of a Mendelian dominantly
inherited predisposition for development of RCs like the Eker rat, which are
predominantly of the clear cell type (this type represents approximately 75 %
of human RCC), and develop from earlier preneoplastic lesions than the Eker
rat. We performed a genetic linkage analysis of the Nihon rat using 113
backcross animals, and found that the Nihon mutation was tightly linked to
genes, which are located on the distal part of rat chromosome 10. Finally, we
identified a germline mutation in the Birt-Hogg-Dubé gene (Bhd) (rat
chromosome 10, human chromosome 17p11.2) caused by the insertion of a single
nucleotide in the Nihon rat gene sequence, resulting in a frame shift and
producing a stop codon 26 amino acids downstream. Thus, the Nihon rat will
contribute to understanding the BHD gene function and renal carcinogenesis.
[Back to top] Renal Neoplasia in the
Hyperparathyroidism-Jaw Tumor Syndrome
M.H. Tan and B.T. Teh
Hyperparathyroidism-jaw tumor (HPT-JT)
syndrome is a familial multi-tumor syndrome resulting from mutations in the HRPT2
tumor suppressor gene, which encodes a protein product named parafibromin. We
review current knowledge of the renal manifestations of the HPT-JT syndrome,
and examine recent advances in understanding the biological function of
parafibromin.