© Borgis - Postępy Nauk Medycznych 11/2010, s. 870-876
*Aleksandra Tołoczko-Grabarek, Joanna Trubicka, Jan Lubiński
Clinical genetics of kidney cancer
Genetyka kliniczna nowotworów nerek
International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Head of the Genetics and Pathology Unit: prof. dr hab. med. Jan Lubiński
Streszczenie
Wśród nowotworów nerki można wyodrębnić 2 główne grupy:
1. Guz Wilmsa – nephroblastoma.
2. Raki nerki – adenocarcinoma (carcinoma clarocellulare, carcinoma papillare, colecting duct carcinoma, chromophobic cell carcinoma), carcinoma urotheliale.
Postać rodzinna guza Wilmsa stanowi 1-2% tych guzów.
Dotychczas opisano 14 genetycznie uwarunkowanych zespołów związanych ze zwiększonym ryzykiem guza Wilmsa. Mutacje konstytucyjne będące przyczyną powstawania dziedzicznego nephroblastoma dotyczą najczęściej jednego z czterech genów: WT1, WT2, FWT1, FWT2. Ryzyko zachorowania na guza Wilmsa u nosicieli tych mutacji wynosi 5-90% w zależności od zmutowanego genu.
Opisano 19 zespołów dziedzicznej predyspozycji do nowotworów, w przebiegu, których w nerkach mogą powstać rak jasnokomórkowy (CCRC), rak brodawkowaty (PRCC) lub rak z nabłonka przejściowego. Najczęściej rozpoznawanym zespołem jest rodzinny rak jasnokomórkowy nerki (F-CCRC). Wśród wszystkich rodzin CCRC 5% spełnia kryteria definitywne F-CCRC, zaś 13% stanowią rodziny podejrzane o F-CCRC.
W większości przypadków F-CCRC nie znaleziono mutacji będących przyczyną agregacji CCRC w rodzinach. W naszych Ośrodku wykazaliśmy, że istotną przyczyną powstawania CCRC jest konstytucyjna zmiana w genie CHEK2. Nadal jednak kluczową rolę w rozpoznawaniu F-CCRC odgrywa analiza rodowodowo-kliniczna. W naszym Ośrodku w rodzinach z pojedynczym CCRC wysuwamy podejrzenie F-CCRC stosując jako kryteria:
a. zdiagnozowanie CCRC poniżej 55. r.ż. lub
b. wystąpienie raka żołądka lub płuca u krewnych I stopnia pacjenta z CCRC.
U osób z rodzin z rozpoznanym F-CCRC stosujemy schemat badań kontrolnych pozwalający na wczesne wykrycie raka nerki, jednak postepowanie lecznicze nie jest ściśle określone.
Ewentualne schematy leczenia będą mogły być ustalone po analizie przebiegu klinicznego leczonych w różny sposób dużych grup raków z rodzin z F-CCRC.
Słowa kluczowe: rak nerek, rak jasnokomórkowy nerki, guz Wilms'a, nefroblastoma
Summary
Among kidney malignancies two main groups can be distinguished:
1. Wilms' tumor – nephroblastoma.
2. Kidney cancer – adenocarcinoma (carcinoma clarocellulare – CCRC, carcinoma papillare – PRCC, collecting duct carcinoma, chromophobe cell carcinoma), carcinoma urotheliale.
Wilms' tumor and kidney cancer can develop as a result of strong hereditary predisposition.
Familial Wilms' tumor constitutes 1-2% of all cases.
Fourteen different syndromes with increased risks of Wilms' tumor have been reported. Hereditary Wilms' tumor is caused by constitutional mutation in WT1, WT2, FWT1 or FWT2 genes. Depending on the mutated gene, the risk of Wilms' tumor varies between 5 and 90%.
Kidney cancer can appear in 19 different hereditary cancer syndromes. One of the most often diagnosed is Familial Clear Cell Renal Cancer Syndrome (F-CCRC). Based on our results, in 5% of cases we can diagnose F-CCRC, and 13% are families with only one affected by CCRC but with a high probability of CCRC in their relatives.
We found that mutations in CHEK2 are associated with an increased risk of CCRC, but still the pedigree and clinical data are crucial for appropriate diagnosis.
The results of our study of CCRC patients revealed that F-CCRC syndrome could be recognized if:
a. CCRC was diagnosed before the age of 55 years.
b. Ist degree relatives of CCRC patient were affected by stomach or lung cancers.
In all individuals with recognized F-CCRC syndrome, specific surveillance is recommended.
Medical treatment for CCRC patients with F-CCRC is not defined yet and should be determined.
Key words: renal cancer, clear cell carcinoma, Wilms' tumor, nephroblastoma
WILMS' TUMOR
Wilms' tumor ( nephroblastoma) is the most common malignant renal neoplasm in children. It is diagnosed with the frequency of 1:10,000 children under the age of 15 years (1). The majority of cases result from de novo mutations and is an isolated case within the family. Familial cases of Wilms' tumor constitute 1-2% of all cases.
Genetic basis for Wilms' tumor
Constitutive mutations leading to hereditary nephroblastoma include mainly one of four genes: WT1, WT2, FWT1, FWT2 (2, 3). In approximately 10% of patients with nephroblastoma the condition is associated with cryptorchidism, hypospadias, facial dysmorphy or developmental defects syndromes: BWS, WAGR. DDS (tab. 1).
Table 1. Genetic syndromes associated with high risk of Wilms' tumor.
SyndromePhenotypeGene/locusInheritanceWilms' tumor risk
Familial aggregation of Wilms' tumors without other clinical pathologiesFamilial aggregation of Wilms' tumors; more frequently unilateral tumors.WT1(11p13)
WT2 (11p15)
FWT1(17q)
FWT2(19q)
ADWT1, WT2 genes mutations ~25%; FWT1 gene mutation - 30%; FWT2 gene mutation 70%
Denys-Drash syndrome (DDS)Wilms' tumor, glomerulopathy, pseudohermaphroditism.Point mutation, WT1 (11p13)Germinal de novo mutation, rare family aggregation, AD90%
WAGRWilms' tumor, aniridia, genitourinary anomalies, mental retardation.Deletion in WT1(11p13)Germinal de novo mutation, rare family aggregation, AD30%
Beckwith-Wiedemann Syndrome (BWS)Macrosomia, macroglossia, midline abdominal wall defects
Other findings: visceromegalia, hipoglycemia, hemihypertrophy, genitourinary anomalies, embryonic tumors.
Locus WT2 (11p15)Germinal de novo mutation, 15% of cases are familial BWS, AD5%
Simpson-Golabi-Behmel (SGB)Gigantism, developmental defects, embryonic tumors.GPC3 (Xq26)XRHigh in boys, undetermined
HPT-JT (hyperparathyroidism-jaw tumor)Adenomas, rarely parathyroid cancer in early years, osteofibrous mandible tumors, Wilms' tumorHRPT2 (1q21-q31)ADHigh, undetermined
PerlmanMacrosomia, visceromegalia, facial dysmorphies, cryptorchidism?AR< 25% in siblings
Trisomy 18Multiple organ defects, mental retardation, Wilms' tumorLow, undetermined
Isolated hemihypertrophyHemihypertrophy??<5%
AniridiaAniridiaPAX6?1.5%
Breast-ovarian cancerBreast and ovarian cancerBRCA1 (17q11), BRCAXADLow
Li-FraumeniSarcoma, leukemias, brain tumors, breast cancerp53 (17p13)ADLow
Neurofibromatosis-type 1Neurofibromas, café-au-lait spots, Lisch nodules, optic gliomaNF1 (17q11)ADLow
BloomShort stature, facial rash, leukemias, lymphomas, colorectal cancer and other cancersBLM (15q26)Low
Wilms' tumor has autosomal dominant pattern of inheritance with incomplete penetrance.
Hereditary nephroblastoma with the above mentioned mutations develop bilaterally more frequently than in sporadic cases (approx. 20% vs. 5%) (1).
Diagnostics principles of the genetic factors for Wilms' tumor
Genetic predisposition for Wilms' tumor is rarely diagnosed as it is underestimated to:
1) take the medical history of distant relatives necessary for familial nephroblastoma detection;
2) link the occurrence of nephroblastoma with the aggregation of other neoplasms, e.g. breast and ovarian cancer or neuromas and sarcomas in families with NF1 mutation;
3) evaluate completely the dysmorphies that enable seeing a genetic predisposition for Wilms' tumor associated with developmental defects.
Like in cases of other familial hereditary cancer syndromes Wilms' tumor diagnosis requires the following steps:
– In-depth analysis of familial medical history data:
a) Wilms' tumor incidence in first- and second-degree relatives, as well as third- and forth-degree;
b) Familial aggregation of other neoplasms;
– Physical examination;
– Cytogenetic assay;
– Molecular DNA assay (4).
Cytogenetic assay is particularly useful when detecting hereditary Wilms' tumors arising due to de novo mutations. It is relatively inexpensive and widely available compared to molecular DNA assay. It was shown that karyotyping is effective in identifying translocations in locus WT2 in patients with BWS, while in situ, hybridization is a sensitive method of detection of large deletions in WT1 gene in people with WAGR syndrome.
In molecular labs conducting scientific research, the complete sequence analysis of WT1, p53 and GPC3 is available enabling point mutation detection. Unfortunately, the remaining genes responsible for hereditary nephroblastoma (WT2, FWT1 and FWT2) have not been cloned yet.
Screening in families with high risk of Wilms' tumor
In families predisposed to Wilms' tumor abdominal ultrasounds should be performed every 3 months from childbirth to the age of 8 years, subsequently every 6 months until 12 years of age (and less frequently afterwards) (1, 5). In cases of unclear lesions or nephrogenic tissue presence (there is some opinions of nephrogenic tissue origin of nephroblastoma), MRI or CT is indicated (1, 6). In Beckwith-Wiedemann Syndrome (BWS) because of the increased risk of other types of cancer the screening should additionally include AFP (alpha-fetoprotein) testing for hepatoblastoma detection. Certain authors recommend performing periodical chest X-rays and VMA (Vanillylmandelic acid) urinalysis test for early neuroblastoma identification (1).
RENAL CELL CARCINOMA (RCC)
Renal cell carcinoma constitutes about 3% of all adult malignancies. In Poland 2,000 new cases are detected every year (7). Clear Cell Renal Carcinoma (CCRC) represents approximately 80% of all diagnosed renal cell carcinomas (7). 1-2% of all RCC is linked with high genetic risk (8).
Thus far 19 syndromes with hereditary cancer predispositions have been described that may lead to the following kidney neoplasms: CCRC, Papillary Renal Cell Carcinoma (PRCC) or collecting duct carcinoma.
Clear Cell Renal Carcinoma (CCRC)
The best known hereditary cancer predisposition syndrome that may lead to CCRC is Von Hippel-Lindau (VHL) disease presented in other chapters of this book (7, 9, 10, 11, 12).
Familial Clear Cell Renal Carcinoma is the most frequently diagnosed syndrome (F-CCRC), in the course of which at least 2 cases of CCRC and the lack of VHL syndrome features are stated (8, 13, 14, 15).
According to our data, the CCRC definitive criteria are met in 5% of all families with CCRC, while in 13% of families there is one case of CCRC with a high risk of subsequent CRCC development.
A genetic predisposition to cancer can be diagnosed more precisely if a constitutive mutation in one of the genes responsible for cancer development is detected. Owing to the availability of mutation analysis in BRCA1, BRCA2, MSH2, or MLH1 genes, an extremely efficient diagnosis of predisposition to breast, ovarian, colorectal and endometrial cancer can be reached.
The gene responsible for F-CCRC occurrence has not been identified yet. In some families' cases cytogenetic assay is helpful in F-CCRC diagnosis.
Currently, there are reports of 3 families with F-CCRC development linked with constitutive translocations. In 1979 Cohen et al. presented familial reciprocal translocation between chromosome 3 and 8 [t(3;8) (p14,2;q24,1)] giving rise to bilateral CCRC at a young age (between 37 and 59) (16). One female mutation carrier had multifocal papillary and anaplastic thyroid cancer. Gemmill et al. in 1998 suggested that t(3;8) leads to the fusion of FHIT and TRC8 genes and probably produces an increasing renal cancer risk. In 1988 Kovacs published a paper presenting a family with constitutive translocation t(3;6) (p13;q25,1). A male carrier of this translocation at the age of 53 years developed bilateral, multifocal CCRC (17, 18).
Another case of familial renal carcinoma caused by translocation was reported in 1998 by the Koolen and Bodmer team (19, 20). In four carriers of reciprocal balanced translocation t(2;3) (q35;q21) RCC developed at the age of 40, 53, 54 and 68 years, including 3 cases of CCRC. One of the carriers had bladder squamous cell carcinoma.
Identical translocation was identified in 1996, in our center, in two brothers with bilateral CCRC, whose 5 other relatives died of renal carcinoma (21).
Van Kessel et al. tested 57 carriers of various reciprocal translocations of chromosome 3 from 10 families. Since four subjects had renal carcinoma a conclusion was drawn that chromosome 3 translocation carriers had an increased risk of renal carcinoma, particularly if the breakage site is located near the centromere (22). The condition develops at an early age (ca. 45), it is multifocal and bilateral.
In the majority of F-CCRC cases presented in literature, an underlying mutation was not found (23, 24, 25, 26, 27, 28). Recently, in our center, it has been shown that constitutive mutation I157T in CHEK2 gene is responsible for CCRC development (29).
However patient history analysis remains the basic method for F-CCRC detection.
Our team defined patient history and clinical symptoms-based criteria resting on first-degree relatives evaluation ("nuclear pedigree” criteria) as enabling the detection of F-CCRC families despite no cases of CCRC in first-degree relatives.
Based on our studies, we proved that in families with a single case of CCRC, F-CCRC can be suspected (fig. 1) when:
Fig. 1. Pedigree charts for families with F-CCRC.
– CCRC is diagnosed below the age of 55 years, or
– gastric or lung cancer occurred in first-degree relatives of the patient with CCRC.
Screening in families with F-CCRC
The characteristic trait of the CCRC condition is its asymptomatic initial period. Clinical manifestations appear along with disease progress. Data from published studies suggests that proper medical management of families with F-CCRC may decrease the risk of developing cancer (25, 30, 31).
However, there are no verified screening programs for early F-CCRC detection.
Levinson suggests that members of a family with F-CCRC should have kidney ultrasounds every 2-3 years starting at the age of 30 years (22). The scheme is accepted by other authors (2, 32), however, it is admitted arbitrarily.
Our analysis suggests that the commencement of screening the members of a family with F-CCRC should depend on when the first appearanceof the disease in the family occured and precede the earliest detection of RCC by 15-20 years but should not start later than at the age of 40 years.
Due to lack of exact knowledge about the development of CCRC in patients from families with F-CCRC the type and frequency of screening tests has not been determined.
In families with F-CCRC when the tumor progresses slowly and metastases appear late, screening tests may be performed less frequently and using less advanced modalities, e.g. abdominal ultrasound.
On the other hand, if carcinomas in F-CCRC families are aggressive from the very beginning and advanced at the time of diagnosis, the detection program should include modalities that enable small size tumor identification. The first line of choice should be contrast-enhanced spiral CT and MRI test (33, 34, 35, 36, 37).
Taking into account the lack of precise data of cancer biology in cases of F-CCRC, in our center we implemented, although arbitrarily, a screening program with the purpose of early kidney-tumors detection in families with VHL disease.
It encompasses kidney ultrasound once a year and CT or MRI once every 3 years (20).
Treatment
Medical treatment schemes for carcinomas in families with F-CCRC have not been determined yet. Treatment schemes could be established based on the results of future clinical studies on large groups and with various treatment options in families with F-CCRC.
If carcinomas in families with F-CCRC prove to be more aggressive, surgery may not be justified and radio- or chemotherapy will have to be administered, or surgical treatment will always have to be more radical.
Conversely, if carcinomas in families with F-CCRC show slow progression and late-onset metastases, "nephron sparing surgery” might be an option that will prevent the patients from undergoing dialysis.
The efficacy of such a treatment was shown in a study on patients with VHL disease. Tumor resection rather than total nephrectomy for early detected tumors is indicated for the condition (32, 38, 39).
Papillary Renal Cell Carcinoma (PRCC)
PRCC incidence is lower than CCRC. PRCC is subdivided into 2 groups: type I – more aggressive, with basophilic cells containing scant cytoplasm and small nuclei, arranged in tubular and papillary structures with numerous macrophages in stroma, and type II – with acidophilic tumors containing large cells with abundant cytoplasm and large nuclei.
Hereditary PRCC (HPRCC) is diagnosed if PRCC occurs in members of the same family in two consecutive generations. The condition is usually type I PRCC (40, 41, 42). In families with HPRCC germinal mutations in the MET gene were reported (31, 43). In some cases the simultaneous occurrence of breast, lung, pancreatic, skin and gastric cancer was described.
Transitional Cell Carcinoma (TCC or Urothelial Cell Carcinoma, UCC)
TCC constitutes one of the usual Lynch syndrome manifestations. Lynch syndrome is associated with colorectal, small intestine, endometrial and urinary tract cancer. More details on the condition can be found in other chapters.
There are 15 other genetic syndromes associated with kidney cancer that were described in the literature.
They are listed in table 2.
Table 2. Genetic syndromes with risk of renal cell cancer (according to Familial Cancer Database FACD, http://facd.uicc.org).
SyndromeFeaturesRCC typeGeneInheritanceIncidence
Von Hippel-Lindau (VHL)Described in VHL sectionCCRCVHLAD1:36 000
Familial clear cell renal carcinoma (F-CCRC), organ-specificFamilial aggregation of CCRC linked with chromosome translocationCCRCT(2:3)
T(3:12)
T(3:6)
T(3:8)
FHIT
TRC8
ADSeveral families
Familial aggregation of CCRC not linked with chromosome translocationCCRCCHEK2MultifactorialUnknown
Hereditary papillary renal cell carcinoma (HPRCC)Familial aggregation of PRCCPRCC type IMETADSeveral families
Hereditary leiomyomatosis and renal cell cancer (HLRCC)Multifocal skin and uterine leiomyomasPRCC type IIFHADUnknown
Lynch syndrome (HNPCC)Described in Lynch syndrome sectionTCCMSH2
MLH1
MSH6
PMS1
PMS2
AD1:400
Tuberous sclerosisNumerous skin, mucosa, CNS, liver, kidney, lungs and retina hamartomasCCRC PRCCTSC1
TSC2
AD1:10 000
Bean syndromeMultiple multifocal skin, intestine, spleen, lung and articular capsule cavernomaUnspecified RCC?ADabout 150 cases
Cowden syndromeMultiple hamartomas, breast cancerUnspecified RCCPTENADabout 300 cases
Gorlin syndromeMultiple basal cell carcinomaUnspecified RCCPTCHAD1:50 000
Fanconi anemiaLow birth weight, short stature, café-au-lait spots bone anomaliesUnspecified RCCFANCA
FANCC
FANCD
FANCG/XRCC9
FANCE
FANCF
AR1:100 000
MEN1Multiple endocrine neoplasiaOncocytoma, unspecified RCCMEN1AD
Familial non-medullary thyroid cancer (FNMTC)PRCCPRCC type I, oncocytomaTCO
FPTC-PRN
AD?One family
Hereditary prostate cancerProstate cancerUnspecified RCCHPC1/HPT1
HPCX
ELAC2/HP2 PCAP
CAPB
HPC20
ADUnknown
Bardet-Biedl syndrome (BBS)Obesity retinopathy, vision loss, brachydactyly, mental retardation, asthma, renal failureCCRCBBS1
BBS2
BBS3
BBS4
BBS5
AR3 cases of RCC in 180 patients with BBS
Werner syndromeShort stature, premature aging, scleroderma type skin lesionsUnspecified RCCWRNAR1:200000
Birt-Hogg-Dube syndromeMultiple skin fibrofolliculomas, trichodiscomas, acrochordonsChromophobic, clear cell, papillary cancerBHD
FLCN
ADSeveral families
Diffuse tubulocystic renal hyperplasia with RCCDiffuse tubulocystic kidney lesionsTubulopapillary cancer?De novoTwo cases worldwide
Colorectal adenoma and carcinoma syndromeColorectal adenoma and carcinomaUnspecified RCCCRAC1ADOne family
Hereditary paragangliomaParaganglioma, pheochromocytoma, neuroblastomaChromophobic, clear cell, papillary cancerSDHA
SDHAF2
SDHB
SDHC
SDHD
ADUnknown
Piśmiennictwo
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otrzymano/received: 2010-10-01
zaakceptowano/accepted: 2010-10-29

Adres/address:
*Aleksandra Tołoczko-Grabarek
International Hereditary Cancer Centre Department of Genetics and Pathology Pomeranian Medical University
ul. Połabska 4, 70-115 Szczecin
tel.: (91) 466-15-32
e-mail: otjg@interia.pl

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