Nuclear Pedigree Criteria for the Identification of Individuals Suspected to be at Risk of an Inherited Predisposition to Renal Cancer
© The Author(s) 2005
Received: 28 July 2005
Accepted: 10 August 2005
Published: 15 August 2005
Renal clear cell carcinomas represent about 3% of all visceral cancers and account for approximately 85% of renal cancers in adults. Environmental and genetic factors are involved in the development of renal cancer. Although to date there are 19 hereditary syndromes described in which renal cell cancer may occur, only four syndromes with an unequivocal genetic predisposition to renal cell carcinoma have been identified: VHL syndrome (mutations in the VHL gene), hereditary clear cell carcinoma (translocations t(3:8), t(2:3)), hereditary papillary carcinoma (mutations in the MET protooncogene) and tuberous sclerosis (mutations in the TSC1 and TSC2 genes). Little is known genetically about the other forms of familial renal cell cancer. Since there is a growing awareness about the necessity of early intervention, clinical criteria have been developed that aid in the identification of hereditary forms of renal cancer. The aim of the current study was to identify minimal inclusion criteria so that nuclear pedigree families can be ascertained for risk assessment and/or kidney tumour screening. The results reveal that inclusion features described herein, such as (a) renal clear cell cancer diagnosed before 55 years of age, and (b) renal clear cell cancer and gastric cancer or lung cancer among first degree relatives, are useful in identifying suspected hereditary clear cell renal cancer patients.
Keywordshereditary clear cell renal cancer diagnostic criteria nuclear families
Genetic syndromes characterised by an increased risk of renal cancer (Familial Cancer Database - FACD, http://facd.uicc.org)
Histological type of renal cancer
Mode of inheritance
Frequency of syndromes
Clear cell carcinoma
B. Hereditary clear cell carcinoma
Clear cell carcinoma
4 families reported
C. Lynch (HNPCC)
D. Tuberous sclerosis
Clear cell carcinoma
H. Fanconi anaemia
M. Syndrome of multiple adenomas and carcinoma of large bowel
N. 'Diffuse tubulocystic renal hyperplasia with renal cell carcinoma'
The identification of genetic predispositions to renal cell cancer remains a priority since knowledge about the underlying molecular genetic basis of the disease will allow for a better understanding of the mechanisms giving rise to the disease and, perhaps more importantly, allow for the identification of individuals who are at risk of disease development.
There are two aspects of these criteria that can be problematic in the clinical setting with respect to the identification of familial renal cell cancer patients. The first is the difficulty in fulfilling criteria in countries where large families and extensive pedigrees are impossible to identify, for whatever reason, even though the incidence of hereditary renal cell cancer may be quite high. Second, the criteria do not take into consideration the existence of family cancer syndromes where renal cell cancer may occur in association with an extra-gastric malignancy.
From a clinical perspective, there is a necessity to be able to identify hereditary renal cell cancer families with a minimum set of criteria that will provide a high likelihood of ascertainment. The aim of this study was to determine whether a minimum set of criteria could be established to identify suspected hereditary renal cell cancer patients when there is restricted information about the familial occurrence of disease.
Patients and methods
A total of 146 clear cell renal carcinoma (CCRC) patients comprising 3 groups were enrolled in the study.
Group A (familial renal cancer): comprising 46 patients affected by CCRC from 22 randomly selected families with at least two renal cancers among first or second degree relatives, independent of age at diagnosis of tumours. All families were registered in the International Hereditary Cancer Centre in Szczecin.
Group A1 (nuclear pedigree): comprising 25 patients affected by CCRC from Group A. None of the parents of these patients have been diagnosed as affected with renal cell cancer.
Group B: a total of 100 individuals diagnosed with CCRC between the years 1993 and 1997 irrespective of family history were collected from the city of Szczecin (total population 400,000).
The following inclusion features (IF) for the identification of suspected hereditary forms of clear cell renal cancer were used and compared against one another for their sensitivity and specificity:
IF 1: at least one of the parents of the patient with CCRC was affected by lung cancer
IF 2: at least one of the parents of the patient with CCRC was affected by gastric cancer
IF 3: CCRC diagnosed at the age of 45 years or younger
IF 4: CCRC diagnosed at the age of 50 years or younger
IF 5: CCRC diagnosed at the age of 55 years or younger
Univariate statistical analysis (Chi-squared, odds ratio (OR), and sensitivity and specificity of selection were performed using the SAS and LOGIT programs.
(n = 46)
(n = 100)
(n = 25)
(n = 100)
IF1V IF2 V IF3
IF1V IF2 V IF3
IF1V IF2 V IF5
The recognition of features that can be used for the identification of familial predispositions to CCRC in situations where extensive pedigree analysis is unknown or impossible to ascertain but the prevalence of the disease is relatively high in the population will aid in the identification of individuals at increased risk of developing CCRC.
By using the criteria described herein and the consequent recognition of significant odds ratios for some of the inclusion features to identify CCRC families, we believe that the identification of additional genes associated with this malignancy will be expedited.
Of particular interest are the odds ratio values for the inclusion features IF5 between groups A1 and B and IF 1 between groups A1 and B, which were relatively high (6.21 and 6.09, respectively). Since these inclusion features are significant we have a relatively high degree of confidence that the reported observations are not biased and are an accurate reflection of the validity of our approach for the identification of hereditary CCRC families. Indeed, these criteria have been tested in our outpatient clinics to successfully identify hereditary CCRC. Therefore if we have families matching IF1 or IF2 or IF5, we are confident that a diagnosis of familial CCRC can be made.
At present it seems reasonable to offer the option of ultrasonography examination to all individuals identified by the use of our inclusion features beginning at the age of 5 to 10 years before the youngest CCRC identified within the patient's family. Such surveillance should only be an option and not a recommendation because the efficiency of such management procedures has not been rigorously determined to reduce morbidity and/or mortality. With respect to surveillance the real value of this will have to be established by studies on large cohorts of individuals from families matching pedigree and clinical criteria of suspected hereditary CCRC with identified constitutional DNA variants associated with genetic predispositions.
So far, the list of genetic changes associated with CCRC is somewhat limited but should be extended in the near future as more knowledge is gained about the genetic factors associated with altered CCRC predisposition.
offer an ultrasound examination option,
create repositories of nuclear clear cell renal cancer families for future studies on the efficiency of surveillance for individuals with genetic predispositions to renal cancer,
perform further studies to aid in the identification of genetic factors associated with CCRC.
- Kumar V, Abbas AK, Fausto N: Pathologic basis of disease. 7th edition. Elsevier Saunders; 2005:1116–1119.Google Scholar
- Choyke PL, Filling-Katz MR, Shawker TH, Gorin MB, Travis WD, Chang R, Seizinger BR, Dwyer AJ, Linehan WM: von Hippel-Lindau disease: radiologic screening for visceral manifestations. Radiology 1990,174(3 Pt 1):815–820.View ArticlePubMedGoogle Scholar
- Neuman HP: Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 1988, 16: 220–226.Google Scholar
- Neumann HP, Zbar B: Renal cysts, renal cancer and von Hippel-Lindau disease. Kidney Int 1997,51(1):16–26. 10.1038/ki.1997.3View ArticlePubMedGoogle Scholar
- Neumann HP, Bender BU, Berger DP, Laubenberger J, Schultze-Seemann W, Wetterauer U, Ferstl FJ, Herbst EW, Schwarzkopf G, Hes FJ, Lips CJ, Lamiell JM, Masek O, Riegler P, Mueller B, Glavac D, Brauch H: Prevalence, morphology and biology of renal cell carcinoma in von Hippel-Lindau disease compared to sporadic renal cell carcinoma. J Urol 1998,160(4):1248–1254. 10.1016/S0022-5347(01)62509-6View ArticlePubMedGoogle Scholar
- Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990, 283: 1151–1163.View ArticleGoogle Scholar
- Poston CD, Jaffe GS, Lubensky IA, Solomon D, Zbar B, Linehan WM, Walther MM: Characterization of the renal pathology of a familial form of renal cell carcinoma associated with von ippel-Lindau disease: clinical and molecular genetic implications. J Urol 1995, 153: 22–26. 10.1097/00005392-199501000-00009View ArticlePubMedGoogle Scholar
- Bodmer D, Eleveld MJ, Ligtenberg MJ, Weterman MA, Janssen BA, Smeets DF, de Wit PE, Berg A, Berg E, Koolen MI, Geurts van Kessel A: An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and t(2:3) (q35;q21) chromosome translocation. Am J um Genet 1998,62(6):1475–1483. 10.1086/301888View ArticleGoogle Scholar
- Borówka A, Zajączek S: Rodzinne występowanie raka jasnokomórkowego nerki. Doniesienie zjazdowe: 26 Kongres PTU, Poznań 1996.Google Scholar
- Braun WE, Strimlan CV, Negron AG, Straffon RA, Zachary AA, Bartee SL, Grecek DR: The association of W17 with familial renal cell carcinoma. Tissue Antigens 1975, 6: 101–104.View ArticlePubMedGoogle Scholar
- Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC, Brown RS: Hereditary renal-cell carcinoma associated with a chromosomal translocation. N Engl J Med 1979, 301: 592–595.View ArticlePubMedGoogle Scholar
- Gemmill RM, West JD, Boldog F, Tanaka N, Robinson LJ, Smith DI, Li F, Drabkin HA: The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. proc Natl Acad Sci USA 1998, 95: 9572–9577. 10.1073/pnas.95.16.9572PubMed CentralView ArticlePubMedGoogle Scholar
- Koolen MI, Meyden AP, Bodmer D, Eleveld M, Looij E, Brunner H, Smits A, Berg E, Smeets D, Geurts van Kessel A: A familial case of renal cell carcinoma and a t(2;3) chromosome translocation. Kidney Int 1998, 53: 273–275. 10.1046/j.1523-1755.1998.00762.xView ArticlePubMedGoogle Scholar
- Kovacs G, Brusa P, De Riese W: Tissue-specific expression of a constitutional 3;6 translocation: development of multiple bilateral renal-cell carcinomas. Int J Cancer 1989, 43: 422–427. 10.1002/ijc.2910430313View ArticlePubMedGoogle Scholar
- Li FP, Marchetto DJ, Brown RS: Familial renal carcinoma. Cancer Genet Cytogenet 1982, 7: 271–275. 10.1016/0165-4608(82)90074-7View ArticlePubMedGoogle Scholar
- Li FP, Decker HJ, Zbar B, Stanton VP Jr, Kovacs G, Seizinger BR, Aburatani H, Sandberg AA, Berg S, Hosoe S, Brown RS: linical and genetic studies of renal cell carcinomas in a family with a constitutional chromosome 3;8 translocation. Genetics of familial renal carcinoma. Ann Intern Med 1993,118(2):106–111.View ArticlePubMedGoogle Scholar
- Maher ER, Yates JR: Familial renal cell carcinoma: clinical and molecular genetic aspects. Br J Cancer 1991, 63: 176–179.PubMed CentralView ArticlePubMedGoogle Scholar
- Yao M, Shuin T: Familial renal cell carcinoma: review of recent molecular genetics. Int J Urol 1995,2(2):61–70. 10.1111/j.1442-2042.1995.tb00426.xView ArticlePubMedGoogle Scholar
- Zbar B, Lerman M: Inherited carcinomas of the kidney. Adv Cancer Res 1998, 75: 163–201. full_textView ArticlePubMedGoogle Scholar
- Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B: Germline and somatic mutations in the tyrosine kinase domain of MET proto-oncogene in papillary renal carcinomas. Nat Gen 1997, 16: 68–73. 10.1038/ng0597-68View ArticleGoogle Scholar
- Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, Zhuang Z, Jeffers M, Woude G, Neumann H, Walther M, Linehan WM, Zbar B: Two north American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res 1998, 58: 1719–1722.PubMedGoogle Scholar
- Zbar B, Lerman M: Inherited carcinomas of the kidney. Adv Cancer Res 1998, 75: 163–201. full_textView ArticlePubMedGoogle Scholar
- Zbar B, Glenn G, Lubensky I, Choyke P, Walther MM, Magnusson G, Bergerheim US, Pettersson S, Amin M, Hurley K: Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 1995,153(3 Pt 2):907–912.PubMedGoogle Scholar
- Zbar B, Tory K, Merino M, Schmidt L, Glenn G, Choyke P, Walther MM, Lerman M, Linehan WM: Hereditary papillary renal cell carcinoma. J Urol 1994, 151: 561–566.PubMedGoogle Scholar
- Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, Kane M, Earabino C, Lipford J, Lindblom A, et al.: Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994, 368: 258–261. 10.1038/368258a0View ArticlePubMedGoogle Scholar
- Hofstra RMW, Wu Y, Berends MJW, Mensink RJG, Sijmons RH, Zee AGJ, et al.: Frequent involvement of MSH6 germline mutations in HNPCC-suspected families with low microsatellite instability tumours. Am J Hum Genet 1998,63(4):A21.Google Scholar
- Lubiński J, Górski B, Kurzawski G, Jakubowska A, Cybulski C, Suchy J, Dębniak T, Grabowska E, Lener M, Nej K: Molecular basis of inherited predispositions for tumors. Acta Biochim Pol 2002,49(3):571–581.PubMedGoogle Scholar
- Lynch HT, de la Chapelle A: Genetic susceptibility to non-polyposis colorectal cancer. J Med Gen 1999, 36: 801–818.Google Scholar
- Park JG, Vasen HF, Park YJ, Park KJ, Peltomaki P, de Leon MP, Rodriguez-Bigas MA, Lubinski J, Beck NE, Bisgaard ML, Miyaki M, Wijnen JT, Baba S, Lindblom A, Madlensky L, Lynch HT: Suspected HNPCC and Amsterdam criteria II: evaluation of mutation detection rate, an international collaborative study. Int J Colorectal Dis 2002,17(2):109–114. 10.1007/s003840100348View ArticlePubMedGoogle Scholar
- Peltomaki P, Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 1997,113(4):1146–1158. 10.1053/gast.1997.v113.pm9322509View ArticlePubMedGoogle Scholar
- van Baal JG, Fleury P, Brummelkamp WH: Tuberous sclerosis and the relation with renal angiomyolipoma. A genetic study on the clinical aspects. Clin Genet 1989, 35: 167–173.View ArticlePubMedGoogle Scholar
- van Baal JG, Smits NJ, Keeman JN, Lindhout D, Verhoef S: The evolution of renal angiomyolipomas in patients with tuberous sclerosis. J Urol 1994, 152: 35–38.PubMedGoogle Scholar
- Bjornsson J, Short MP, Kwiatkowski DJ, Henske EP: Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. Am J Pathol 1996,149(4):1201–1208.PubMed CentralPubMedGoogle Scholar
- Sampson JR, Patel A, Mee AD: Multifocal renal cell carcinoma in sibs from a chromosome 9 linked (TSC1) tuberous sclerosis family. J Med Genet 1995, 32: 848–850. 10.1136/jmg.32.11.848PubMed CentralView ArticlePubMedGoogle Scholar
- Weinblatt ME, Kahn E, Kochen J: Renal cell carcinoma in patients with tuberous sclerosis. Pediatrics 1987,80(6):898–903.PubMedGoogle Scholar
- Hoffman T, Chasko S, Safai B: Association of blue rubber bleb nevus syndrome with chronic lymphocytic leukemia and hypernephroma. Johns Hopkins Med J 1978,142(3):91–94.PubMedGoogle Scholar
- Haibach H, Burns TW, Carlson HE, Burman KD, Deftos LJ: Multiple hamartoma syndrome (Cowden's disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). Am J Clin Pathol 1992,97(5):705–712.PubMedGoogle Scholar
- Gorlin RJ: Nevoid basal-cell carcinoma syndrome. Medicine 1987,66(2):98–113. 10.1097/00005792-198703000-00002View ArticlePubMedGoogle Scholar
- Deeg HJ, Socie G, Schoch G, Henry-Amar M, Witherspoon RP, Devergie A, Sullivan KM, Gluckman E, Storb R: Malignancies after marrow transplantation for aplastic anemia and Fanconi anemia: a joint Seattle and Paris analysis of result in 700 patients. Blood 1996,87(1):386–392.PubMedGoogle Scholar
- Swift M, Caldwell RJ, Chase C: Reassessment of cancer predisposition of Fanconi anemia heterozygotes. J Natl Cancer Inst 1980,65(5):863–867.PubMedGoogle Scholar
- Alter BP: Fanconi's anemia and malignancies. Am J Hematol 1996, 53: 99–110. 10.1002/(SICI)1096-8652(199610)53:2<99::AID-AJH7>3.0.CO;2-ZView ArticlePubMedGoogle Scholar
- Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS, Wang Y, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong Q, Spiegel AM, Burns AL, Marx SJ: Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997,276(5311):404–407. 10.1126/science.276.5311.404View ArticlePubMedGoogle Scholar
- Duquenne M, Weryha G, Leclere J, Duriez T, Schneegans O: Oncocytome renal au cours d'une neoplasie endocrinienne multiple de type I (letter). Presse Med 1992,21(27):1293–1294.PubMedGoogle Scholar
- Jeddi A, Vasse N, Prunet D, Buzelin F, Bouchot O, Buzelin JM: Wermer syndrome associated with a bilateral renal tumor. Prog Urol 1996,6(1):103–106.PubMedGoogle Scholar
- Reed WB, Walker R, Horowitz R: Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venerol 1973, 53: 409–416.PubMedGoogle Scholar
- Epstein CJ, Martin GM, Schultz AL, Motulsky AG: Werner's syndrome: a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine 1966,45(3):177–221.PubMedGoogle Scholar
- Goto M, Miller RW, Ishikawa Y, Sugano H: Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev 1996,5(4):239–246.PubMedGoogle Scholar
- Ishii T, Hosoda Y: Werner's syndrome: autopsy report of one case, with a review of pathologic findings reported in the literature. J Am Geriatr Soc 1975,23(4):145–154.View ArticlePubMedGoogle Scholar
- Ishikawa Y, Sugano H, Matsumoto T, Furuichi Y, Miller RW, Goto M: Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race. Cancer 1999,85(6):1345–1352. 10.1002/(SICI)1097-0142(19990315)85:6<1345::AID-CNCR18>3.0.CO;2-#View ArticlePubMedGoogle Scholar
- Birt AR, Hogg GR, Dube WJ: Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977, 113: 1674–1677. 10.1001/archderm.113.12.1674View ArticlePubMedGoogle Scholar
- Cohen PR, Kurzrock R: Miscellaneous genodermatoses: Beckwith-Wiedemann syndrome, Birth-Hogg-Dube syndrome, familial atypical multiple mole melanoma syndrome, hereditary tylosis, incontinentia pigmenti, and supernumerary nipples. Dermatol Clin 1995,13(1):211–229.PubMedGoogle Scholar
- Tomlinson I, Rahman N, Frayling I, Mangion J, Barfoot R, Hamoudi R, Seal S, Northover J, Thomas HJ, Neale K, Hodgson S, Talbot I, Houlston R, Stratton MR: Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15q14-q22. Gastroenterology 1999, 116: 789–795. 10.1016/S0016-5085(99)70061-2View ArticlePubMedGoogle Scholar
- Henske EP, Thorner P, Patterson K, Zhuang Z, Bernstein J: Renal cell carcinoma in children with diffuse cystic hyperplasia of the kidneys. Pediatr Dev Pathol 1999,2(3):270–274. 10.1007/s100249900123View ArticlePubMedGoogle Scholar