**3. Basic cancer genetics**

approximately 60–70 years. The most common kidney tumor of childhood is Wilms' tumor (nephroblastoma). In the European Union, the estimated annual number of new kidney cancers is approximately 46,000 [2]. Etiologic risk factors for kidney cancer development are male sex, obesity, and tobacco, in addition to hypertension [3–5], acquired cystic kidney disease [6], and inherited susceptibility. Prognostic factors of different protein and gene expressions in

According to the latest knowledge, hereditary kidney cancers may account for 5–8% of all kidney cancers [9], and it may be more common than previously thought [10]. In those RCC patients without clear cell RCC (ccRCC) subtype, the amount of germline high-risk mutations is greater, 12% [11]. Susceptibility to kidney cancer may be caused by high-risk, moderate-risk, or low-risk gene mutation [12]. Even the carriership of high-risk gene mutation does not always lead to kidney cancer. The risk for kidney cancer (penetrance) varies in different syndromes. In some cases, the predisposed genetic factor to kidney cancer is chromosomal aberration, for example, as in constitutional chromosomal 3 translocation with 6 or 8 of family

More than 15 syndromes with inherited susceptibility to kidney cancer are known, and there are over 25 known genes associated with them. Most of these are dominantly inherited in which the offspring of the proband has a 50% chance of inheriting a gene mutation with

Hereditary kidney cancer syndrome is often characterized by an early age of onset (approximately 45 years) [30], typical histological pattern, and frequently the bilaterality and multicentricity of the primary tumor (**Table 1**). By evaluating the family history of diagnosed cancer cases, benign tumors, and diagnostic gene test results, it is possible to identify families

It is possible that there exists only a single hereditary cancer syndrome case in the family due to de novo mutations (autosomal dominant) which means that the person's parents do not have the same mutation. There are hot spot regions in genes where mutation can easier develop during meiosis of germ cells. In addition to this, the risk of hereditary kidney cancer

(**Table 2**). In hereditary cancer, the impact of environmental factors is small.

RCC have been studied [7, 8].

4 Evolving Trends in Kidney Cancer

susceptibility to kidney cancer.

**2. Identifying hereditary kidney cancer**

with hereditary kidney cancer (**Tables 2** and **3**).

Multiple close relatives with benign or malign tumors of the syndrome

Typical histological finding (e.g., rare subtype or multiplicity) or clinical picture

• Colon cancer or endometrial carcinoma in the uterus and upper tract urothelial carcinoma

Atypically young age of onset for tumors of the syndrome Relative with two tumors of the syndrome (two examples below)

**Table 1.** Factors suggesting inherited cancer syndrome.

• RCC and uterine leiomyosarcoma

In hereditary and sporadic cancer, the normal genome regulation is impaired [34], and cancer susceptibility is caused by both inherited germline gene mutations and somatic gene mutations in tissue that occurred over time. However, in sporadic cases the inherited gene mutations cause low risk for kidney cancer [35]. Of all clear cell-type RCCs (sporadic or hereditary), 75% have a somatic mutation in the von Hippel-Lindau tumor suppressor gene (VHL) in the short


arm of chromosome [36]. According to Vogelstein's research group, chance has a major impact in the development of cancer-causing mutations during DNA replication in normal, noncancerous stem cells [37]. Current understanding is that about four to seven mutations in

• In the carriers of Lynch syndrome mutation, removal of colon adenomas decreases the risk of colon cancer

• In the carriers of Lynch syndrome mutation, removal of uterus by menopause decreases the risk of endometrial

Genetic Susceptibility to Kidney Cancer http://dx.doi.org/10.5772/intechopen.91933 7

Genes associated with cancer predisposition are oncogenes or tumor suppressor genes. Oncogenes act as gain of function. Mutation in the other allele is sufficient to produce the altered protein. An example of this is the *MET* oncogene, in which mutation predisposes to hereditary papillary renal cell carcinoma (HPRC) (**Table 2**). However, typically inherited cancer predisposition is caused by the loss of function of tumor suppressor gene. In nearly all cases, the mutations in tumor suppressor genes function recessively at the cellular level, following Knudson's theory of two hits [39]. Therefore, both alleles must lose function before the carcinogenesis may occur. The first mutation associated with the syndrome, the germline mutation, passes the susceptibility to cancer to the next generation (nearly always) according to the autosomal dominant inheritance and is situated in all the persons' cells. The mutation in the other allele in the same gene occurs during life. The penetrance of the inherited mutation is decreased. Therefore, only part of the mutation carriers will be affected, but the risk of cancer is

Caretaker genes are responsible for genomic stability by detecting damage to the genome, such as single- or double-stranded DNA breaks [40]. Disruption in these genes leads to genomic instability: an increase in the number of spontaneous mutations that cause new mutations in oncogenes and growth restriction genes. Mutations in the caretaker genes are responsible for a number of cancer susceptibility syndromes. For example, germline mutation in the growth restriction gene *MLH1* exposes for Lynch syndrome, which is associated with a high risk of colon and endometrial carcinoma in the uterus and multiple risk for urothelial carcinoma compared to an average population [24, 41]. Gatekeeper genes control cell growth. Normally, a mutation in a gatekeeper gene activates the caretaker genes to participate in repair [34]. However, if this repair does not work, mutation in the gatekeeper gene will result in tumor formation. For example, *p53* acts as a gatekeeper, and its mutation exposes it to several types of

key driver genes is sufficient to cause cancer to develop [38].

**Table 5.** How to improve prognosis in the carriers of hereditary gene mutation.

Occurrence can be prevented by removing the precursors identified in the monitoring

• In the carriers of p53 mutation, radiation therapy and X-ray imaging will be avoided

The aim is to improve the early detection of cancer

Occurrence can be prevented by surgical procedures

Sometimes genetic information can guide the choice of medication

carcinoma in uterus

many times higher than in an average population (**Tables 2** and **3**).

cancers, such as RCC (**Table 3**).

**Table 3.** Hereditary cancer syndromes in which the kidney cancer risk is moderate or low.


**Table 4.** Congenital multisystem syndromes with susceptibility for the kidney cancer.

The aim is to improve the early detection of cancer

Occurrence can be prevented by removing the precursors identified in the monitoring

• In the carriers of Lynch syndrome mutation, removal of colon adenomas decreases the risk of colon cancer

Occurrence can be prevented by surgical procedures

**Tuberous sclerosis Beckwith-Wiedemann syndrome Perlman syndrome**

Clear cell, papillary, chromophobe Wilms' tumor Wilms' tumor

Less than 5% Around 5% 30–60%

35 years Primarily in the first 8 years of life Neonatally

Neonatal hypoglycemia, macrosomia, macroglossia, hemihyperplasia, omphalocele, Fetal ascites, macrosomia, visceromegaly, generalized hypotonia

renal abnormalities

Inheritance Autosomal dominant Autosomal dominant, sporadic Autosomal recessive

Gene *TSC1*, *TSC2 CDKN1C DIS3L2*

References [31, 32] [33] [33]

**Table 4.** Congenital multisystem syndromes with susceptibility for the kidney cancer.

Kidney cancer subtype

**Lynch syndrome**

6 Evolving Trends in Kidney Cancer

Upper tract urothelial carcinoma

*MSH2*, *MSH6*, *PMS2*, *EPCAM*

Bowel cancer, uterine, ovarian cancer

Kidney cancer subtype

Risk for kidney cancer

Other signs of the syndrome than RCC

Gene *MLH1*,

**Cowden syndrome**

Clear cell, papillary, chromophobe

Mucocutaneous papules, hamartomas, macrocephaly, thyroid cancer, uterine cancer, intestinal polyps

**Hyperparathyroid jaw tumor syndrome**

Papillary type 1 RCC, adult Wilms'

Ossifying jaw fibromas, renal cysts, parathyroid adenoma/carcinoma, uterine tumors

Reference [24] [25] [26] [27] [28] [29]

**Table 3.** Hereditary cancer syndromes in which the kidney cancer risk is moderate or low.

Multiple 15% Uncommon 10% Low 10%

*PTEN CDC73 SDHB*, *SDHC*, *SDHD p53 BAP1*

GIST

tumor

**Hereditary pheochromocytoma and paraganglioma**

Clear cell RCC, chromophobe RCC, oncocytoma

Paragangliomas, pheochromocytoma, **Li-Fraumeni syndrome**

RCC and Wilms' tumor

Brain tumor, sarcoma, leukemia and other cancer types

**BAP1 tumor predisposition syndrome**

Clear cell RCC

Uveal and cutaneous melanoma, mesothelioma

Risk for kidney cancer

Typical age of onset for kidney cancer

Other signs of the syndrome than kidney cancer

Renal angiomyolipomas,

hypopigmentation, seizures, learning difficulties, angiofibromas, shagreen patches, oral mucosal lesions, subependymal giant cell astrocytoma • In the carriers of Lynch syndrome mutation, removal of uterus by menopause decreases the risk of endometrial carcinoma in uterus

Sometimes genetic information can guide the choice of medication

• In the carriers of p53 mutation, radiation therapy and X-ray imaging will be avoided

**Table 5.** How to improve prognosis in the carriers of hereditary gene mutation.

arm of chromosome [36]. According to Vogelstein's research group, chance has a major impact in the development of cancer-causing mutations during DNA replication in normal, noncancerous stem cells [37]. Current understanding is that about four to seven mutations in key driver genes is sufficient to cause cancer to develop [38].

Genes associated with cancer predisposition are oncogenes or tumor suppressor genes. Oncogenes act as gain of function. Mutation in the other allele is sufficient to produce the altered protein. An example of this is the *MET* oncogene, in which mutation predisposes to hereditary papillary renal cell carcinoma (HPRC) (**Table 2**). However, typically inherited cancer predisposition is caused by the loss of function of tumor suppressor gene. In nearly all cases, the mutations in tumor suppressor genes function recessively at the cellular level, following Knudson's theory of two hits [39]. Therefore, both alleles must lose function before the carcinogenesis may occur. The first mutation associated with the syndrome, the germline mutation, passes the susceptibility to cancer to the next generation (nearly always) according to the autosomal dominant inheritance and is situated in all the persons' cells. The mutation in the other allele in the same gene occurs during life. The penetrance of the inherited mutation is decreased. Therefore, only part of the mutation carriers will be affected, but the risk of cancer is many times higher than in an average population (**Tables 2** and **3**).

Caretaker genes are responsible for genomic stability by detecting damage to the genome, such as single- or double-stranded DNA breaks [40]. Disruption in these genes leads to genomic instability: an increase in the number of spontaneous mutations that cause new mutations in oncogenes and growth restriction genes. Mutations in the caretaker genes are responsible for a number of cancer susceptibility syndromes. For example, germline mutation in the growth restriction gene *MLH1* exposes for Lynch syndrome, which is associated with a high risk of colon and endometrial carcinoma in the uterus and multiple risk for urothelial carcinoma compared to an average population [24, 41]. Gatekeeper genes control cell growth. Normally, a mutation in a gatekeeper gene activates the caretaker genes to participate in repair [34]. However, if this repair does not work, mutation in the gatekeeper gene will result in tumor formation. For example, *p53* acts as a gatekeeper, and its mutation exposes it to several types of cancers, such as RCC (**Table 3**).

Genetics of cancer is only partially known. Advanced technological methods can detect previously unknown mutations in germline and tumors. Knowledge of the biology of hereditary cancer also increases the understanding of sporadic cancers, as the same disease genes are found in hereditary and non-hereditary cancers: e.g., mutated *MET* is a driver gene in hereditary and sporadic papillary renal carcinomas [42], and mutated *WT1* is observed both in sporadic and hereditary Wilms' tumor. Novel genes and variants may be explored by whole exome (WES) or genome research (WGS), where also noncoding regions are examined, in scientific research projects. Identifying low-risk variants requires data from thousands of patients and controls, which are investigated in genome-wide association studies (GWAS).

in the family. If there are no surviving cancer patients in the family, with the permission of the relative, from the pathology department, a sample of the deceased person may be requested to

Genetic Susceptibility to Kidney Cancer http://dx.doi.org/10.5772/intechopen.91933 9

The result of the genetic testing gives information about the cancer risk of relatives. Healthy atrisk relatives should have access to genetic counseling and predictive genetic testing after counseling if they decide (Council of Europe's The Convention on Human Rights and Biomedicine in Article 12, 1997). The clinical genetics units offer this service. The geneticist will have the opportunity to provide the laboratory with reliable information about the family mutation and arrange for the laboratory the DNA sample of the family's index patient, which is a control sample, positive control, to obtain a reliable test result. Counseling before predictive genetic testing is nondirective and includes insight of the patient and the family. In counseling, the patient and family receive not only information but also support. Increased anxiety or distress has been documented in both counselors and their families around testing when investigating hereditary VHL susceptibility [45]. The Genetic Information Nondiscrimination Act of the Council of Europe's Convention in Article 11, in 1997, was passed to prevent forms of genetic discrimination by employment and health insurance. The Council of Europe's Convention prohibits the transfer of genetic information to employers in order to prevent employment discrimination. Insurance discrimination is discussed in counseling. In Finland, genetic testing is organized by public health care, which is why very few gene tests are conducted privately. Participation in predictive genetic testing has been studied in the Finnish Lynch syndrome families, which are at high risk for colorectal cancer and endometrial carcinoma in the uterus. Approximately 80% of the members of the family participated in genetic counseling, and 95% of them performed genetic prediction [46]. The main reasons for participating in predictive genetic testing are the potential for cancer detection in surveillance monitoring, improved treatment options in many Lynch syndrome cancer types, and improved cancer prognosis.

After the genetic testing, the counselor should always receive an interpretation of the significance of the genetic test result [43, 44]. Different mutations in the same disease gene, for example, in the inherited VHL gene, can have varying effects on cancer risk and prognosis [47]. The genetic practitioner will assess the significance of the result for each family separately. It is useful to wait until the age of 18 to allow an offspring to reach an age of consent in those inherited syndromes in which the age of onset is in adulthood. However, the early age of onset in condition like VHL could have devastating complications without early detection and management, and therefore in

*VHL* is divided to subgroups for academic purposes according to the phenotype based on the likelihood of pheochromocytoma or renal cell carcinoma. In the following some examples are described. For example, a reduced risk for renal cell carcinoma in individuals has been observed with a deletion of *VHL* [13]. A *MET* variant due to a mutation is associated with early-onset HPRC disease [16]. The *WT1* gene mutation may cause hereditary Wilms' tumor

this syndrome predictive testing is recommended to at-risk children in family.

**5. Genotype***-***phenotype correlation in kidney cancer**

have healthy tissue DNA for genetic examination.
