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© 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.
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.
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.

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Piśmiennictwo
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otrzymano: 2010-10-01
zaakceptowano do druku: 2010-10-29

Adres do korespondencji:
*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

Postępy Nauk Medycznych 11/2010
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