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

*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 without syndrome or with syndrome, like Denys-Drash, Frasier, or nephrotic syndrome type 4. WT1 protein plays an important role in renal and gonadal development, due to which genital abnormalities can be seen in Denys-Drash and Frasier syndrome. In Frasier syndrome patients have progressive nephrotic syndrome, but incidence of Wilms' tumor is rare. Mutations that are responsible for Frasier syndrome are located in intron 9 in *WT1* (an alternative splicing site). In Denys-Drash syndrome, patients' typical symptoms are progressive nephrotic syndrome that early progresses to renal failure less than the age of 4 years. A majority of the Denys-Drash patients have mutations located in exons 8 and 9. The risk of Wilms' tumor is very high (90%).

During counseling, the geneticist will inform what is known about the significance of the identified variant. If the significance of the variant remains open, the geneticist and laboratory experts may reclassify the change after few years. The increased use of multigene NGS panels in patient work expands the knowledge on the different pathogenic variants in the human DNA. The number of VUS changes will therefore decrease in the next few years [50]. It is important that counseling provides reliable information on the examination results and therefore VUS modifications are not used as a basis for prophylactic surgery or to determine the risk of relatives' cancer.

Genetic Susceptibility to Kidney Cancer http://dx.doi.org/10.5772/intechopen.91933 11

For several RCC syndromes, studies have found that conservative management appears to preserve renal function without increased mortality. In certain syndromes, such as HLRCC, early and aggressive treatment may be preferable [17, 20]. Each subtype of RCC may need to be treated differently by systemic therapy, but no phase III clinical trial data exist from distinct treatments [51, 52]. The prognosis was inferior for papillary metastatic RCC (mRCC) compared to clear cell mRCC when patients were treated with the same evidence-based treatment in a study by Staehler [52]. The understanding of the metabolic and epigenetic abnormalities underlying the symptoms of hereditary kidney cancer-associated genes may lead to the development of novel diagnostic biomarkers and novel treatment modalities for

Recommendations for follow-up care should correspond to the level of risk associated with the genetic variant tested [43]. The aim of the monitoring is to improve the early detection of cancer in families with hereditary renal cancer. Monitoring recommendations includes regular kidney imaging: the healthy carrier of a gene mutation predisposing to kidney cancer will usually undergo abdominal MRI scans on a regular basis (**Table 7**). The frequency of follow-up depends on the biological nature of the family syndrome. Several monitoring planes have been proposed for hereditary kidney cancer syndromes, for example, by Freifeld [54] and Carlo [10]. Also, PDQ Cancer Information Summaries [55] has a suggestion for surveillance in certain

Tracking intervals may be less frequent, for example, for HPRC, and more frequent for others, such as HLRCC in the case of an early onset of 10 years [56] and several reported cases among children. However, the estimated risk of developing RCC before age 20 is estimated to be only around 1–2%, whereas the lifetime risk of RCC among *FH* mutation carriers is approximately 15% [25]. In 2014, consensus guidelines from an international HLRCC symposium recommended annual renal MRI starting at age 8 to 10 years, as also recommended by the HLRCC Family Alliance and the French National Cancer Institute [25]. The starting age is still variable. In HPRC patients, if the tumor smaller than 3 cm is found, imaging should be repeated within the first year to assess the growth rate [55]. Generally, patients with renal

**7. Treatment in hereditary kidney cancer**

**8. Surveillance in hereditary kidney cancer families**

syndromes predisposing to hereditary renal cancer.

kidney cancer [53].

## **6. The diagnostic impact of gene testing evolution**

Multigene next generation sequencing (NGS) panel technology allows genes of interest to be studied quickly and cost-effectively. By focused massive parallel sequencing, it is possible to examine those exons of the genome's genes that are of interest in diagnosing the cause of inherited kidney cancer. The method can also investigate boundaries between exons and introns. A gene panel for hereditary kidney cancer covers approximately 25 genes and can be ordered from different companies. Clinical picture may sometimes indicate a mutation in particular gene or genes, which can be separately examined. However, often hereditary mutation may be in many different genes according to patient and family history, and then multigene panel-based NGS will be more economical than Sanger or NGS sequencing of several different genes. Sequencing results are obtained in about 4 weeks. The gene content of the panels is regularly updated by laboratories as information on genes associated with kidney cancer is published continuously. A limitation of parallel sequencing is that they cannot recognize large intrinsic deletions or duplicates, and for this another method is required that investigates exome CNVs. A majority of hereditary mutations are located in the exome region. The whole genome NGS is not yet a routine method, but it is used in scientific studies. By the NGS method, the diagnostic utility of hereditary cancers has been hugely improved.

Information on the clinical significance associated with mutations is reviewed in registers (e.g., InSiGHT and ClinVar) [48]. With the development of research techniques, more variants of uncertain significance (VUS) are now observed. Currently, these are also variants of which it is unknown whether they are benign or pathogenic and explain the patient's predisposition to cancer. In some situations, the variant may be classified as likely pathogenic. Prediction programs can be used to evaluate a variant's ability to cause disease (in silico analysis) [49, 50]. For example, the ExAC database can be used to check the prevalence of the variant in the population. As techniques evolve, it is increasingly possible to study the functional change in RNA structure caused by VUS alteration, which would be relevant to the quality of the resulting protein. In order to clarify the nature of the uncertain variants, the geneticist may arrange the so-called segregation analysis in family [49]. Finding the same hereditary variant from several relatives with cancer would strengthen the conclusion that the variant explains the cases in the family. Information is being collected internationally as laboratories collect VUS they observe into databases and doctors publish case reports. However, in already well-known genes such as BRCA and Lynch syndrome genes, VUS alterations are relatively rarely detected.

During counseling, the geneticist will inform what is known about the significance of the identified variant. If the significance of the variant remains open, the geneticist and laboratory experts may reclassify the change after few years. The increased use of multigene NGS panels in patient work expands the knowledge on the different pathogenic variants in the human DNA. The number of VUS changes will therefore decrease in the next few years [50]. It is important that counseling provides reliable information on the examination results and therefore VUS modifications are not used as a basis for prophylactic surgery or to determine the risk of relatives' cancer.
