GENETIC SYNDROMES ASSOCIATED WITH RENAL CELL CARCINOMA – A REVIEW

Aims. A review of recent knowledge on heredital syndromes related to renal cell carcinoma. Methods. Aim of this review was to summarize the recent knowledge of genetic syndromes associated with renal cell carcinoma. Results. Summary of incidence and factors modulating risk of hereditary renal cell carcinoma development. Conclusions. Hereditary forms of RCC are relatively rare. Their study is beneficial in many ways. In individuals at a higher risk of a hereditary syndrome, the knowledge of hereditary forms may help to significantly decrease the impact of the hereditary disease. In the general population, knowledge acquired by the study of hereditary forms of RCC may in the future contribute to both diagnosis and treatment of sporadic tumours.


INTRODUCTION
Kidney cancer belongs to 16 most frequent malignancies in the Czech Republic and globally.In 2008, a total of 265,731 persons were diagnosed with this type of cancer and 113,315 people died (IARC) (ref. 1 ).And the incidence continues to rise.
Renal cell carcinoma (RCC) is not a single entity but rather a group of tumours originating from kidney epithelium 2 .RCC originates from the tubular structures of the kidney and is classified into 4 main histological types.4][5] ) of all RCC cases, is clear cell renal cell carcinoma (ccRCC).

CHARACTERISTICS OF HEREDITARY FORMS OF RCC
Approximately 4% of all RCC are hereditary 2,7 .Men are twice as likely as women to become affected.The incidence of sporadic forms of RCC begins to increase after 30 years of age, with cases occurring most rapidly after the age of 45 and peaking after 70 years.This Table 1.Classification schema for kidney epithelial neoplasias.
Pavlovich and Schmidt listed 7 hereditary syndromes associated with RCC, in 5 of which genes causing the syndromes had been revealed 2 .The presented article expands the list to 11 syndromes and more than 10 genes associated with the development of these syndromes.
Renal cell carcinoma is not a single disease but an entire collection of different types of cancer, each of which is caused by a different gene and has a different histology and clinical course.Each of the genes (VHL, MET, FLCN, TSC1, TSC2, FH and SDH) is, in a way or another, involved in pathways responding to metabolic stress or nutrient stimulation.
Mutations in each of these genes result in dysregulation of metabolic pathways involved in oxygen, iron, energy or nutrient sensing, suggesting that RCC is a disease of cell metabolism 8 .
Hereditary forms of RCC usually have a typical structure and occur at a much younger age as compared with sporadic forms.Since hereditary RCC is usually a tumour syndrome, besides renal manifestation, there are otherextrarenal -manifestations of the syndrome.Frequently, extrarenal manifestations may prevail and RCC develops in only a small proportion of patients suffering from a particular syndrome.
Hereditary syndromes associated with increased or earlier development of RCC are summarized in (Table 2).Hereditary RCC occurs at a younger age whereas in the normal population, RCC is seen between the ages of 60 and 70.More frequently, hereditary RCC is multifocal and bilateral.Moreover, unlike sporadic RCC that is twice as frequent in males, the gender distribution is equal 9,10 .
If a hereditary type of tumour is suspected, tumour histology and possibly extrarenal symptoms may be helpful in the differential diagnosis to rule out sporadic forms 11 .
All the listed syndromes are autosomal dominant, with the exception of RCC associated with involvement of chromosome 3 (ref. 11).

Von Hippel-Lindau (VHL) syndrome
In VHL syndrome, an increased incidence of ccRCC is observed.

Hereditary papillary renal carcinoma (HPRC)
Families with HRPC syndrome suffer from type 1 papillary RCC.The syndrome is caused by mutation of the MET (mesenchymal-epithelial transition factor) proto-oncogene 2,11,14 .The mutation is typical for familial papillary RCC.
Apart from type 1 papillary carcinoma, neither other typical manifestations nor the exact incidence of this hereditary RCC are known.HPRC typically develops between the 5th and 6th decade of life.The disorder is highly penetrant.Persons affected by HPRC sndrome have a 90% (ref. 16,17) likelihood of developing RCC by the age of 80 years 8,18 .

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)
Individuals affected by HLRCC syndrome are at increased risk of type 2 papillary RCC.This type is rarer but more aggressive 18,19 .
HLRCC syndrome is caused by mutations in the fumarate hydratase (FH) gene on chromosome 1q42-43.
In addition to renal involvement, it is common for patients with HLRCC to have uterine leiomyomas, leiomyosarcomas and cutaneous leiomyomas 2,11,13,14,20 .
(Some families, however, are only affected by cutaneous and uterine leiomyomas, rarely with RCC.In such cases, the syndrome is called multiple cutaneous and uterine leiomyomatosis 2 ).
HLRCC usually occurs at a young age (the youngest known case was at the age of 16 years 13 , with a median incidence at the age of 39 years 14 ).
Various histological types of RCC may be present within a single family affected by BHD syndrome, in a single patient or even in the same kidney 28,13 .
Tumour lesions may be solitary or bilateral and multifocal.Genetic syndromes associated with renal cell carcinoma -a review Members of families affected by BHD syndrome have a 7-fold increased risk of RCC as compared with the normal population 26 .
In addition to RCC, the BHD manifestations include cutaneous papules (fibrofolliculomas, most commonly on the head, neck and anterior trunk) in about 85% (ref. 13) of BHD patients and lung cysts in more than 80% (ref. 13) of patients.About 25% (ref. 13) of patients have a history of spontaneous pneumothorax.Although some families were found to have a higher prevalence of colon cancer it is not known yet whether this may be considered a BHD syndrome manifestation 28 .
Approximately 95% (ref. 29) of persons with HPT-JT develop hyperparathyroidism, 5% (ref. 29) of patients develop parathyroid carcinoma and about half of the patients are known to have fibro-osseous mandibular and maxillary tumours.
HPT-JT is associated with mutations in the HRPT2 (hyperparathyroidism 2) tumour suppressor gene.Since only about 50 families have been reported so far, the exact incidence has not been determined 30 .

Constitutional chromosome 3 translocation
Balanced chromosome 3 translocations are a rare cause of ccRCC (OMIM 603046 and 144700) 31,32,14 .A total of 13 different constitutional translocations involving chromosome 3 have been described, of which 7 are associated with familial kidney cancer and the remaining 6 were not found to run in families 33,34 .
At present, little is known about RCC caused by constitutional chromosomal translocations.The only clue is the presence of chromosome 3 translocation and multifocal and bilateral ccRCC.
The search for other genes responsible for hereditary forms of kidney cancer/renal cell carcinoma has not been completed.Several other genetic abnormalities will likely be associated with familial kidney cancer.

Familial papillary thyroid cancer (FPTC)
Persons affected by the syndrome have higher rates of papillary RCC and renal oncocytoma.In addition to tumours of the kidney, they develop papillary thyroid cancer and nodular thyroid disease.Of all cases of papillary thyroid cancer, only 5% (ref. 2 ) are of hereditary origin.
The FPTC phenotype has been linked to 1q21 (ref. 37), indicating a new RCC-associated gene could be responsible for this syndrome 14 .

Familial RCC of as yet unknown genetic cause
Familial ccRCC is defined as the development of ccRCC in two or more members of the same family, in whom VHL disease and constitutional chromosome 3 translocation have been ruled out 38,39,7,14 .This type of tumour is associated with a very low frequency (over 70 families have been reported).In those families, first-degree relatives have a 2-3-fold increased risk of RCC than the normal population 40 .As the cause remains unknown, the multigenetic mechanism of inheritance is assumed 2 .

Tuberous sclerosis (TS)
This hereditary syndrome is associated with mutations in the TSC1 and TSC2 genes 41,42 .
Although the incidence is consistent with sporadic forms of RCC, they develop at a young age -28 years of age on average 45 .Most frequent is ccRCC but chromophobe RCC, papillary RCC and oncocytomas were also reported 46 .
A total of 90% (ref. 11) of TS patients suffer from epilepsy.Only 30% (ref. 11) of cases have the classical triad of epilepsy, mental retardation and sebaceous adenoma.Skin manifestations include hypomelanotic macules, facial angiofibromas, shagreen patches and fibrous plaques.In the mouth, gingival fibromas may be found.Other potential extrarenal manifestations are periventricular hamartomas, cardiac rhabdomyomas and retinal hamartomas.As many as 75% (ref. 11) of patients are found to have renal asymptomatic angiomyolipomas.

Hereditary paraganglioma/pheochromocytoma
Originally, two families with hereditary paragangliomas were found to have a higher prevalence of ccRCC.In those persons, three out of four genes encoding succinate dehydrogenase, a Krebs cycle enzyme, were mutated (SDHB, SDHC, SDHD) (ref. 47).Later research revealed bilateral, multifocal ccRCC or chromophobe RCC with a very early onset 48 .
Other -extrarenal -tumours include paragangliomas and pheochromocytomas.The patients are diagnosed with kidney cancer before the age of 30.As the disease is rare, the prevalence is as yet unknown.

Familial renal oncocytoma (FRO)
The syndrome is usually associated with solitary, multifocal and bilateral oncocytomas.As of now, FRO syndrome is only known to be autosomal dominant but the particular gene has not been identified.Potential overlap with BHD is being studied 49 .On average, persons with FRO develop kidney cancer at the age of 55.8 years 50 .Apart from kidney cancer, no other manifestations are known.
Due to the low frequency (only about 20 cases are known), the exact prevalence of the syndrome has not been determined.

DISCUSSION
The importance of the study of hereditary forms of RCC is in identifying pathways involved in the particular type of tumours.Subsequently, the pathways are also studied in sporadic forms of the tumour.The knowledge of the development and mechanism of involvement of genetic pathways leads us to the metabolic effect resulting from the genetic disorder and gives us a chance to distinguish various forms of the same histological type of cancer.As a result, the so-called tailored therapy may be applied in each individual patient.
The exact mechanism of the development of hereditary RCC is still not completely known.The key steps are activation of the cell proliferation cascade and prevention of apoptosis 2,21,51 .Impaired regulation of proliferation and angiogenesis are two main components of carcinogenesis in the kidneys 21 .
The findings may also be applied in prevention of kidney cancer in families affected by any of the syndromes.The question is how to tell that an individual has a hereditary form of RCC.
A hereditary form of RCC should be suspected if: 1) the patient has a personal or family history of RCC, 2) there is bilateral or/multifocal RCC, 3) there is early-onset RCC (under 50 years of age 2,52,53 ).
Additionally, RCC should be suspected if the patient or his/her relatives has any of extrarenal manifestations typical for certain forms of syndromes, such as fibrofolliculomas or pneumothorax 14 .
According to Axwijk et al., screening should be recommended to 11 : 1) patients with a mutation in one of the mentioned genes, associated with a RCC syndrome, 2) patients and first-degree relatives from a family with a suspected RCC syndrome, which could not be confirmed by genetic analysis, 3) patients and first-degree relatives in a family with two or more first-or second-degree relatives with RCC, 4) individuals with RCC before the age of 50 and their first-degree relatives.
For diagnosis and secondary prevention, ultrasound and CT are the examination of choice in persons with kidney disease manifestations.At present, however, these preventive (screening) measures can mostly be applied in persons with an increased risk of developing this serious condition.

CONCLUSION
Although hereditary forms of RCC are relatively rare, their study is beneficial in many ways.In individuals at a higher risk of a hereditary syndrome, the knowledge of hereditary forms may help to significantly decrease the impact of the hereditary disease.In the general population, knowledge acquired by the study of hereditary forms of RCC may in the future contribute to both diagnosis and treatment of sporadic tumours.

Table 2 .
Hereditary cancer syndromes in RCC.

Table 2 .
(continued)is due to accumulation of genetic and epigenetic changes in the cells of ageing individuals and failing repair and defence mechanisms.However, this is not true for hereditary forms of RCC.Hereditary RCC is rather rare and specific.Hereditary forms of RCC typically occur at a younger age.More frequently, hereditary RCC is multifocal and bilateral.Most of the known forms of hereditary RCC are linked to syndromes (with the exception of balanced translocations of chromosome 3).