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The Oncologist, Vol. 13, No. 3, 239-247, March 2008; doi:10.1634/theoncologist.2007-0242
© 2008 AlphaMed Press

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Clinical Genetics and Genetic Counseling

Familial Risks for Cancer as the Basis for Evidence-Based Clinical Referral and Counseling

Kari Hemminkia,b, Jan Sundquistb, Justo Lorenzo Bermejoa

aDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; bCenter for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden

Key Words. Familial risk • Clinical genetic counseling • Referral of familial cancers • Genetic testing • Prevention

Correspondence: Correspondence: Kari Hemminki, M.D., Ph.D., DKFZ Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. Telephone: 49-6221-421800; Fax: 49-6221-421810; e-mail: k.hemminki{at}dkfz.de

Received December 11, 2007; accepted for publication January 30, 2008.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   Learning Objectives
Top
 Footnotes
 Learning Objectives
Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
After completing this course, the reader will be able to:

  1. Describe the relative risk (using the standardized incidence ratio) of various familial cancers defined by the affected family member.
  2. Evaluate family history as a risk factor for all cancers, not only the ones for which mutation or PSA testing is recommended.
  3. Critically assess the accuracy of reported family histories.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Footnotes
 Learning Objectives
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
Objective. Reliable, clinically useful data on familial risks have not been available for all types of cancer, and familial aggregations of cancers, which are not known to belong to an inherited cancer syndrome, are often overlooked by medical referral systems. We provide uniform data on familial risks in all common cancers.

Methods. The nationwide Swedish Family-Cancer Database includes 11.5 million individuals, born in 1932 and later, along with their parents. Standardized incidence ratios (SIRs) were calculated for age-specific familial risks in offspring.

Results. The familial risks for offspring cancer were increased at 24 of 25 sites when a parent was diagnosed with concordant cancer, at 20 of 24 sites when a sibling was affected, and at 14 of 16 sites when a parent and at least one other sibling were affected. Among the offspring of affected parents, testicular cancer showed the highest risk, 4.52, followed by Hodgkin's disease (3.95) and esophageal cancer (3.36). At many sites, the risks between siblings were higher than those between offspring and affected parents, probably in part because of childhood environmental effects.

Conclusions. The data show convincingly that familial clustering is a common feature for all cancer sites. The results will be helpful in implementing evidence-based guidelines for clinical genetic counseling and in facilitating the recognition of familial risk at all levels of the general medical referral system.


   INTRODUCTION
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 
Familial cancer is an avenue to the understanding of cancer etiology, giving the first indication of the possible involvement of heritable genes [1–3]. However, cancer is a common disease and most families have members who have been diagnosed with cancer. The cumulative risk for cancer (risk for cancer in the absence of other causes of death) up to the age of 85 years is 51% for men and 38% for women according to the Swedish Cancer Registry [4]. The cumulative risk for prostate cancer alone is 23%, and that for female breast cancer is 13%. Thus, for a true familial risk, the number of affected family members needs to be higher than what could be expected by chance alone. Based on the magnitude of the risk, families may be categorized into high risk, constituting hereditary cancer syndromes [5–7], and moderate risk, constituting familial clusters without clear Mendelian patterns [8, 9]. Familial clustering of cancer has become an issue in oncology clinics because of the success in implementing genetic testing and screening methods for many cancer syndromes [6, 10–12]. Public awareness of familial risks and the demand for counseling of patients and their family members have increased [13]. A family history is a risk factor for which advice and management may bring both medical and psychosocial benefits. However, in order to provide advice, the counselors and the caregivers along the medical referral system need to be aware of the true familial risks, particularly for cancers that are not covered in familial risk management guidelines [12].

In the present article, we provide age-specific familial risks for all common cancers. The data are presented separately according to the type of affected family members (parent–offspring, sibling), in order to make them applicable to the clinical setting. The source of the empirical data is the recent update of the Swedish Family-Cancer Database, the world's largest dataset on familial cancer, covering the whole Swedish population as families and containing data on medically diagnosed cancers in this population [14]. The results show that familial risk is a characteristic of all cancers. For some cancers, it is the only known or the largest known risk factor. Moreover, for cancers such as breast and colorectal cancers, which are manifested both in defined heritable syndromes and in non-Mendelian familial aggregations, the latter affects many more families than the former. In the present calculations, we do not attempt to separate the effects of such Mendelian components but we do comment on the likely outcome if such a separation was to be done. Data are not shown for leukemia, because its many subtypes would require a separate treatment [15], nor are they shown for eye cancer, because the familial risk is mainly contributed by the Mendelian syndrome, retinoblastoma [16].


   PATIENTS AND METHODS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Acknowledgments
 References
 
Statistics Sweden maintains a "Multigeneration Register" where children (offspring) born in Sweden since 1932 (i.e., maximally 72 years of age) are registered with their parents (those confirming parenthood at birth) as families [14]. The data on families and cancers have complete coverage, barring some groups of deceased offspring, which affect those born in the 1930s and who died before 1991. Although this small group of offspring with missing links to parents has a negligible effect on the estimates of familial risk [17], we limited the present study to offspring for whom both parents are known. This Register was linked by the individually unique national registration number to the Cancer Registry for the years 1958–2004. However, because of some inaccuracies in vital status determination in the first years of cancer registration, cancers were recorded for the years 1961–2004 in the most recent update carried out in 2006 [18]. Cancer registration is currently considered to be close to 100% [4]. Four-digit diagnostic codes according to the seventh revision of the International Classification of Diseases (ICD-7) and subsequent ICD classifications are available. For thyroid cancer, only nonmedullary tumors were considered because hereditary medullary thyroid cancer of very high risk has been covered before [19]. For skin cancer, only squamous cell carcinomas are recorded in the Cancer Registry. Additional linkage was carried out to the national census data, to obtain socioeconomic background data, and to death notifications, for vital status determination.

Standardized incidence ratios (SIRs) were used to measure the cancer risks for offspring according to the occurrence of cancers in their families. SIRs were calculated for offspring whose parent only, sibling only, or parent and sibling had the same, concordant cancer, that is, using parents only, siblings only, or parents and siblings as probands. Follow-up was started for each offspring at birth, immigration, or January 1, 1961, whichever came latest. Follow-up was terminated on diagnosis of first cancer, death, emigration, or the closing date of the study, December 31, 2004. Parents' ages were not limited, but offspring were 0–72 years of age. Data are shown for ICD-7 sites only if at least 10 familial parent–offspring pairs were identified for the particular proband status. SIRs were calculated as the ratio of the observed to expected number of cases. The expected numbers were calculated from 5-year-age-, sex-, period- (5 year bands), socioeconomic status- (six groups), and region- (three groups) specific incidence rates in the general Swedish population [20]. Offspring risks are shown separately for specific age groups that were selected depending on the age at onset of the particular cancer. Ninety-five percent confidence intervals (95% CIs) were calculated assuming a Poisson distribution [20]. Risks for siblings were calculated using the cohort method, described elsewhere [21]. In this method, families with multiple affected individuals are ascertained at multiple times and they are not independent, leading to too narrow CIs; CIs were adjusted for this reason [22].


   RESULTS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Acknowledgments
 References
 
The year 2006 update of the Swedish Family-Cancer Database (MigMed2) includes 11.5 million individuals, organized into 3.5 million families. Cancers for this population were retrieved from the Swedish Cancer Registry, totaling 201,268 first invasive cancers in the offspring generation, aged up to 72 years; the number of cancers in the parental generation of unlimited age amounted to 680,000 [18]. Familial risks were calculated for offspring when only a parent, only a sibling, or both a parent and sibling were affected by a concordant cancer (Table 1). Cancer sites were divided into three groups based on the median age at onset of the particular cancer in the offspring population (<40, 40–50, and >50 years).


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  		Table 1. Numbers of cases and relative risks for individuals whose parents or siblings were affected by concordant cancer

 
Among the offspring of affected parents, 24 of the 25 cancer sites showed a significant familial risk (Table 1). Testicular cancer had the highest risk, 4.52, followed by Hodgkin's disease (3.95) and esophageal cancer (3.36). Liver cancer showed the smallest significant risk, 1.30. Only the SIR for connective tissue tumors was not significant. Familial risks for siblings were significant for 20 of the 24 cancer sites. By far the highest risk was noted for nonmedullary thyroid cancer (15.6), but even the SIRs for testicular cancer (6.63), Hodgkin's disease (6.51), ovarian cancer (4.89), and kidney cancer (4.70) were remarkably high. SIRs for connective tissue and liver tumors were not increased and no sibling pairs were diagnosed for esophageal cancer. Cancers in one parent and at least two offspring may signal high penetrance effects; 14 of the 16 sites showed a significant risk. SIRs >10 were recorded for endocrine gland, ovarian, colon, renal, endometrial, upper aerodigestive tract, and liver tumors; however, the latter two constituted single families.

Familial risks for siblings should not be compared with those of offspring of affected parents because the ages of the probands were different (Table 1). In Table 2, we have adjusted the ages of parents maximally to 72 years to make them comparable with the offspring population, thus allowing comparison of the risks. In this table, the underlined sibling SIRs indicate that the sibling excess risk (SIR – 1.00) is higher than the excess risk for offspring of affected parents by a factor of 1.5; a significant difference (p < .05) between these SIRs is marked by an asterisk.


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  		Table 2. Numbers of cases and relative risks for individuals whose parents or siblings were affected by concordant cancer when the parental age was limited to 72 years

 
Large differences between these two SIRs were noted for nonmedullary thyroid, ovarian, prostate, lung, rectal, and kidney cancers. The difference was also significant for breast cancer.

Table 3 shows familial risks for offspring in three age groups when parental ages were not limited. The age groups were adjusted according to the typical age at onset of the particular cancer. Two different patterns were observed: about one half of the cancers showed a higher familial risk in younger age groups and a decline in risk toward higher ages (e.g., breast, prostate, and colon cancers), whereas, for the other half, diagnostic age appeared not to be important and the SIRs were relatively equal among the age groups (e.g., melanoma and cervical and lung cancers); for a few sites, the small number of cases hampered conclusions; for example, the V-shaped trend for testicular cancer was based on a small number of cases. High SIRs were noted in the youngest covered age group for testicular cancer (5.75), Hodgkin's disease (6.87), connective tissue tumors (5.25 in the age group 26–35 years), and thyroid gland tumors (6.30).


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  		Table 3. Age-specific relative risks for offspring of parents affected by a concordant cancer at any age

 
Table 4 shows the effects of age on sibling risk when one of the siblings was diagnosed in the given age band; the cosibling (proband) could be diagnosed at any age up to 72 years. The numbers of cases were smaller than those in Table 3, making some of the effects of diagnostic age less regular. Although many sites follow the decreasing or even patterns of risk with increasing age, as was seen in Table 3, for melanoma and ovarian, endometrial, and bladder cancers, there appears to be a shift in the pattern. In Table 4, a clear age-dependent risk was noted, as compared with the relatively even patterns in Table 3. For testicular cancer, the V-shaped pattern remained. Some of the early-onset SIRs were very high: 67.5 for nonmedullary thyroid cancer, 11.2 for ovarian cancer. The SIRs were >5.0 for Hodgkin's disease and testicular, renal, rectal, and bladder cancers. Even the sibling risks for pancreatic and prostate cancers exceeded an SIR of 5.0 in the age group 46–55 years.


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  		Table 4. Age-specific relative risks for siblings affected by a concordant cancer

 

   DISCUSSION
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Acknowledgments
 References
 
The hereditary cancer syndromes are now potentially addressed by genetic testing, but for the moderate-risk familial cancers, empirical epidemiologic data are an important component in risk estimation [6, 9]. The clinically used risk-estimation models for breast cancer are based on epidemiological data of a woman's individual risk factors, including a family history [23, 24], and they were further extended after the identification of the highly penetrant breast cancer susceptibility genes and other risk factors [25]. Similarly for prostate cancer, data on individual risk factors and a family history have been incorporated into the risk-estimation models [26]. For many cancers, few individual risk factors, other than age, are known, and the empirical data on familial risk may be uniquely relevant.

Clinical genetic counseling and the management of familial cancer need to rest on a solid scientific foundation. It was estimated a few years ago that, of some 600 global studies reporting familial risks for cancer during the last two decades, about 500 have been case-control studies [9]. Recent case-control studies are based on verified diagnoses in the cases, but only few of them have verified the diagnoses in the relatives. Even many cohort studies lack verification of cancers in family members. There is ample literature illustrating the problem of false reporting, the consequences of which have been largely ignored. Murff et al. [27] collected literature on the accuracy of family history data for cancer by comparing reported histories with the related medical documentation. The positive predictive value (percentage of positives among true positives) of the reported family history compared with the medical diagnosis in a first-degree relative was 93% for breast, 85% for prostate, 81% for colon, 69% for ovarian, and 37% for endometrial cancer when reported by cancer patients. These figures confirm several similar studies that demonstrate that cancers of the breast and colon are usually accurately reported while cancers in the abdominopelvic regions are not. When family histories were reported by healthy controls, the positive predictive values were about 20%-units lower; the worst were ovarian (25%) and endometrial (17%) cancers, confirming the lack of accuracy in reporting abdominal and pelvic tumors. These values were even lower for second-degree relatives than for first-degree relatives. Many of the findings were similar in a Swedish study, which suggested that reporting is worse for rare cancers; somewhat surprisingly, the accuracy of reporting cancer in siblings was worse than that in parents [28].

Population-level data of the present kind do not allow a direct identification of the known cancer syndromes among site-specific cancers. However, having access to the whole population over several generations allows application of guidelines that have been developed for recommending patients for mutation testing, for example for the BRCA-1/2 and hereditary nonpolyposis colorectal cancer (HNPCC) genes. Such guidelines increase the likelihood of mutation detection by requiring data on the number of affected family members and the types of cancers, each with age at onset. Using such definitions, it has been possible to estimate the contribution of many syndromes to the observed familial aggregation, for example, BRCA-1/2 for breast and ovarian cancers [29, 30], HNPCC for colorectal and endometrial cancers [31, 32], and von Hippel-Lindau (VHL) for renal cancer [33]. Based on such analyses, we estimate that the very high risks for ovarian, colon and endometrial, kidney, and endocrine gland tumors may be explained by BRCA-1/2, HNPCC, VHL, and RET mutations, respectively. Even though these or any other syndromes constitute a small proportion of the relevant familial cancers, because of their high penetrance, they may nevertheless constitute a large proportion of cases in families where a parent and two or more offspring are affected (parent and sibling as probands). The p16 locus is linked to familial melanoma [34], and several syndromes predispose to nervous system cancers [35–37]. However, we do not precisely know to what extent the high familial risks are explained by these causes.

A number of cancer susceptibility genes/loci have recently been described, including CHEK-2 for many cancers [38, 39], ATM, BRIP-1, PALB-2, NSB-1, CASP-8, TGF-β1, FGFR-2, and loci on chromosomes 2 and 16 for breast cancer [40–46]; MUTYH for colorectal cancer [47]; and up to seven loci on chromosome 8 for prostate cancer [48, 49], with association also for colorectal cancer [50]. However, the variant alleles of these genes are so rare or the risks are so low that their contribution to the familial risk is not high [2, 51]. The present study points out several cancers with high familial risk for which practically no susceptibility genes are known, including nonmedullary thyroid, testicular, lung, bladder, skin (squamous cell), and esophageal cancers, non-Hodgkin's lymphoma, Hodgkin's disease, and myeloma.

The data in Table 2 show that, for some cancer sites, the familial SIR differs extensively depending on the proband, parent or sibling. Such a difference may have etiologic implications, for example, in terms of recessive inheritance or an early childhood environmental effect, both of which would cause higher risks between siblings than between offspring and affected parents [52]. The high sibling risks for nonmedullary thyroid and rectal cancers are particularly suggestive of recessive effects, because few environmental risk factors are known for these cancers. Even though high-penetrance genes predispose to nervous system, ovarian, and kidney cancers, the genes act in a dominant fashion and would not explain the high sibling risks. Environmental factors may contribute to the sibling risks for lung and pancreatic cancers (smoking), skin cancer (solar exposure), Hodgkin's disease (Epstein Barr virus), and stomach cancer (Helicobacter pylori); seeking a medical examination and greater surveillance by an unaffected sibling may increase the opportunity for early detection, thus leading to higher sibling risks for breast and prostate cancers [53]. Concern is warranted because of the relatively small case numbers. For example, recessive inheritance has been considered likely for testicular cancer because of the high risk between brothers compared with the risk between sons and fathers, which even was noted earlier in the present Database [54, 55]. Irrespective of the etiological scenarios, for immediate clinical genetic counseling, the magnitude of the familial risk is more important than its cause, implying that the appropriate familial risk estimates should be used for presenting families.

How large a risk should trigger clinical action? In the present paper, we have calculated relative risks without considering the prevalence of the particular cancer. A relative risk of 2.0 for breast cancer by age 70 years (cumulative risk of about 8% [4]) would imply a doubling of the number of cases from 8 to 16 per 100 women by the age of 70 years. In a similar setting, a tenfold higher risk for nonmedullary thyroid cancer (cumulative risk, about 0.2%) would result in less than two additional cases per 100. In the recent American Cancer Society Guidelines for Early Detection of Cancer, familial risk was mentioned as an indication for intensified screening for four cancers: breast, colorectal, endometrial, and prostate cancers [56]. For breast cancer, the magnitude of the risk was not defined, and for endometrial cancer, only the likely HNPCC carriers were considered. For colorectal cancer, the indication was defined as a diagnosis in a first-degree relative before the age of 60 years. The recommendation called for "more intensified surveillance" over the scheme that was proposed for average-risk adults from age 50 years onward. For prostate cancer, an annual digital rectal examination and prostate-specific antigen test were recommended starting at the age of 45 years if a first-degree relative was diagnosed before 65 years of age; for average-risk adults, these same diagnostic procedures were recommended from the age of 50 years onward.

The above guidelines were not specifically intended for familial cancer and they are limited as to the number of sites and specification of an action level. For some cancer sites for which genetic testing is offered, management recommendations are given [9], but these cover a small proportion of familial cancers. We argued earlier for ad hoc evidence-based guidelines for the counseling and management of familial cancers that would need to penetrate the entire medical referral chain [9]. Such guidelines could be based on the present kind of data on familial risk, but they need to be adjusted by the experiences of the counselors who are routinely dealing with familial cancers in the moderate risk category.


   ACKNOWLEDGMENTS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
References
 
Supported by Deutsche Krebshilfe, the Swedish Cancer Society, The Swedish Council for Working Life and Social Research, and the EU, LSHC-CT-2004-503465. The Family-Cancer Database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.


   FOOTNOTES
 
Conception/design: Kari Hemminki

Provision of study materials or patients: Jan Sundquist

Collection/assembly of data: Jan Sundquist

Data analysis and interpretation: Kari Hemminki, Justo Lorenzo Bermejo

Manuscript writing: Kari Hemminki, Justo Lorenzo Bermejo

Final approval of manuscript: Kari Hemminki, Jan Sundquist, Justo Lorenzo Bermejo


   REFERENCES
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Acknowledgments
 References
 

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