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Platinum Priority – Editorial and Reply from AuthorsReferring to the article published on pp. 987–993 of this issue

Familial Clustering of Sporadic Kidney Cancer: Insufficient

Evidence to Recommend Routine Screening in Unaffected Kin

Marc C. Smaldone a, Veda N. Giri b, Robert G. Uzzo a,*

a Division of Urologic Oncology, Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA; b Cancer Prevention and Control Program

and Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA

Renal cell carcinoma (RCC) is a heterogeneous disease

composed of differing histologic subtypes, each of which is

associated with unique genetic mutations, clinical features,

and sensitivity to treatment [1]. Genetic linkage analyses in

families with hereditary kidney cancer syndromes includ-

ing von Hippel-Lindau (VHL), hereditary papillary RCC,

hereditary leiomyomatosis and RCC, and Birt-Hogg-Dube

have resulted in the identification of several kidney cancer

susceptibility genes with either tumor suppressor (VHL,

fumarate hydratase) or proto-oncogene (MET) functions.

Further examination of these genetic pathways has

suggested that kidney cancer is essentially a metabolic

disorder, and this has facilitated the development of targets

for molecular agents currently used in patients with both

hereditary and sporadic advanced disease [2].

Although these seminal works in hereditary kidney cancer

have resulted in the identification of genetic alterations

responsible for carcinogenesis inherited in an autosomal

dominant pattern, our understanding of the epigenetic

alterations and familial inheritance patterns resulting in

sporadic RCC remains limited. Early efforts in registry-based

studies to characterize familial risk of RCC have reported

roughly a two-fold increased risk for subjects with affected

first-degree relatives [3,4]. However, findings of case-control

studies designed to confirm these findings have been mixed

[5,6] and highlight the fact that elevated familial relative risk

may be due to a genetic component or to shared environ-

mental exposures or may be multifactorial [6].

In this issue of European Urology, Liu et al [7] expand on

previous efforts [3] to characterize familial risk for RCC by

linking data from three national population registries in

Sweden (Multi-Generation Register, Swedish Cancer Regis-

try, and Swedish Hospital Discharge Register). Using

DOI of original article: 10.1016/j.eururo.2011.05.031* Corresponding author. Department of Surgery, Division of Urologic OncologUSA. Tel. +1 215 728 3501; Fax: +1 215 214 1734.E-mail address: Robert.Uzzo@fccc.edu (R.G. Uzzo).

0302-2838/$ – see back matter # 2011 European Association of Urology. Publ

International Classification of Disease (ICD) coding, the authors

identified 8513 national cases of RCC from 1961 to 2008, of

which 229 were designated as familial cases (2.7%). After

adjusting for risk factors associated with RCC including age,

gender, socioeconomic status, obesity, and smoking, the

authors report elevated standardized incidence ratios (SIRs)

of 1.75 and 2.61 when parents or siblings, respectively, had a

documented diagnosis of RCC as well as a SIR of 10.74 when

both a parent and a sibling had a history of RCC. The authors

report that these findings remained significant even when

accounting for histologic subtype, and findings did not differ

after excluding families with VHL syndrome, chronic

obstructive pulmonary disease (COPD), and obesity. Further-

more, study findings demonstrated associations with pros-

tate cancer (parent proband) and other malignancies such as

melanoma, non-Hodgkin lymphoma, urothelial carcinoma of

the bladder, and papillary thyroid cancers (sibling proband).

The authors concluded that RCC demonstrates familial

clustering beyond known hereditary syndromes and that

recessive effects may play a role in these familial aggregation

patterns [7].

Use of large multigeneration national registries, which do

not exist in the United States, provide a unique opportunity to

examine the incidence of differing types of malignancies and

their familial relationships at a population level. The authors

of this interesting and thought-provoking study [7] should be

commended for their rigorous assessment of data from >12

million Swedish patients as well as their efforts to account for

other factors that influence the development of RCC such as

obesity, smoking, and hereditary syndromes. When closely

examining these relationships, it becomes prudent to ask the

question: Is there clinical relevance beyond statistical

significance at this point in time? The authors have

y, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111,

ished by Elsevier B.V. All rights reserved.

E U R O P E A N U R O L O G Y 6 0 ( 2 0 1 1 ) 9 9 4 – 9 9 7 995

succeeded in demonstrating that there may be a statistically

significantly increased familial risk of RCC that is greatest

with affected siblings, and they infer that by accounting for

VHL (hereditary) cases, these effects may be due to genetic

variants with a recessive inheritance pattern.

Several factors may limit drawing such conclusions. The

predisposition to develop RCC differs among patient

populations, and of >12 million patients, only 229 cases

of RCC were identified in patients with parents or siblings

diagnosed with RCC (familial cases) [7]. Of these, 136 (59%)

were designated as likely due to VHL syndrome (associated

with hemangioblastoma or pheochromocytoma). This

leaves only 93 putative cases from which to derive a

population-based linkage. In addition, although elevated

risks in siblings as opposed to offspring can be indicative of

a recessive rather than dominant effect [8], a more rigorous

approach to control for confounding environmental effects

is needed (as opposed to relying on administrative claims

data to capture COPD as a surrogate for smoking) when

familial clustering of cancer diagnoses is observed. Finally,

the authors report similar familial risks of kidney cancer in

the offspring and siblings diagnosed with any malignancy

(not just kidney cancer), and this clouds the implications for

screening in patients with a family history of sporadic RCC

and requires further study for confirmation.

Following a cancer diagnosis, patients frequently ask

physicians if siblings or offspring should be screened for

malignancy. Outside of hereditary syndromes with known

genetic mutations accounting for disease risk in families,

these data are insufficient to recommend routine screening in

families with familial RCC outside of a clinical study or

registry. Formal study of screening in familial hereditary RCC

may be warranted to address such issues as age to begin

screening, who to screen, optimal interval, and type of

screening test or tests to perform. In addition, other genomics

strategies such as genomewide association studies may

ultimately identify RCC-specific predisposition loci [9] and in

turn could provide improved risk-prediction accuracy in

families with familial RCC from which to make appropriate

DOIs of original articles: 10.1016/j.eururo.2011.05.031,10.1016/j.eururo.2011.06.026* Corresponding author. Division of Molecular Genetic Epidemiology,German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.Tel. +49 6221 421809; Fax: +49 6221 421810.E-mail address: h.liu@dkfz.de (H. Liu).

screening and perhaps prevention recommendations. Until

then, when patients ask whether their families should be

screened for kidney cancer, an objective discussion of the data

should ensue and should include this study, which fails to

demonstrate a definitive association. The counseling process

should encompass the unknown benefits of screening and

should emphasize that any RCC screening should ideally be

performed on a protocol, preferably with genomic screening,

to advance risk assessment for familial kidney cancers.

Conflicts of interest: The authors have nothing to disclose.

References

[1] Linehan WM, Pinto PA, Bratslavsky G, et al. Hereditary kidney

cancer: unique opportunity for disease-based therapy. Cancer 2009;

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[2] Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney

cancer: a metabolic disease. Nat Rev Urol 2010;7:277–85.

[3] Czene K, Hemminki K. Kidney cancer in the Swedish Family Cancer

Database: familial risks and second primary malignancies. Kidney

Int 2002;61:1806–13.

[4] Gudbjartsson T, Jonasdottir TJ, Thoroddsen A, et al. A population-

based familial aggregation analysis indicates genetic contribution in

a majority of renal cell carcinomas. Int J Cancer 2002;100:476–9.

[5] Clague J, Lin J, Cassidy A, et al. Family history and risk of renal cell

carcinoma: results from a case-control study and systematic meta-

analysis. Cancer Epidemiol Biomarkers Prev 2009;18:801–7.

[6] Hung RJ, Moore L, Boffetta P, et al. Family history and the risk of

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[7] Liu H, Sundquist J, Hemminki K. Familial renal cell carcinoma from

the Swedish family-cancer database. Eur Urol 2011;60:987–93.

[8] Risch N. The genetic epidemiology of cancer: interpreting family and

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doi:10.1016/j.eururo.2011.06.026

Platinum Priority

Reply from Authors re: Marc C. Smaldone, Veda N. Giri,Robert G. Uzzo. Familial Clustering of Sporadic Kidney

Cancer: Insufficient Evidence to Recommend RoutineScreening in Unaffected Kin. Eur Urol 2011;60:994–5

Kari Hemminki a,b, Hao Liu a,*

a Division of Molecular Genetic Epidemiology, German Cancer Research

Center (DKFZ), 69120 Heidelberg, Germany; b Center for Primary Health

Care Research, Lund University, Malmo, Sweden

Familial cancer has become an issue in oncology clinics

because of the success in implementing genetic testing and

screening methods for many cancer syndromes [1]. Public

awareness of familial risks and the demand for counseling

of patients and their family members have increased. A

family history is a risk factor for which advice and

management may bring both medical and psychosocial

benefits. Unfortunately, physicians and even oncologists

and genetic counselors in many developed countries are

unaware of the familial aggregation of cancer beyond the

known cancer syndromes.

For appropriate advice, the counselors and the caregivers

along the medical referral system need to be aware of the

true familial risks, which particularly concern cancers that

are not covered by the available familial risk management