Article Summary: Genetic Testing in Kidney Cancer

Introduction Kidney cancer accounts for 2.
2% of new cancer cases worldwide and 1.
8% of deaths
.

In recent years, the incidence of kidney cancer in China has shown a trend of continuous growth.
Early-stage kidney cancer can be surgically removed and has a better prognosis
.

About 20%-30% of renal cancers will recur and metastasize after surgery
.

Metastatic renal cancer (mRCC) is insensitive to conventional radiotherapy and chemotherapy, with poor prognosis and high mortality, posing a great threat and impact on the life of patients
.

With the advent of the era of precision medicine, individualized treatment has gradually become the trend of tumor treatment
.

The widespread application of genetic testing technology represented by next-generation sequencing (NGS) provides technical support for the precise treatment of tumors
.

In non-small cell lung cancer, breast cancer, prostate cancer and many other cancers, molecular pathology provided by genetic testing has become an essential part of subsequent treatment decisions, and more suitable treatment plans can be provided according to different molecular pathological types
.

Although molecular typing based on genetic testing has not been used as a reference for mRCC treatment in domestic and foreign guidelines and consensuses, in recent domestic and foreign studies, gene mutations have a certain role in the clinical diagnosis, efficacy evaluation, and prognosis prediction of renal cancer.
clinical value
.

Selection of patients who are suitable for genetic testing 1.
Second-line or later-line treatment of metastatic clear cell carcinoma (mccRCC) About 70% of renal cell carcinomas are clear cell renal cell carcinoma, and systemic drug therapy is the standard treatment for mccRCC, and the current treatment drugs It mainly includes tyrosine kinase inhibitors (TKIs), mTOR inhibitors and immune checkpoint inhibitors (ICIs)
.

Once treatment is resistant, subsequent second-line or even later-line treatment options are not clearly stated in the guidelines
.

For mccRCC patients who have progressed on first-line therapy, genetic testing may be considered to predict drug sensitivity and optimize treatment drug selection
.

2.
Metastatic non-clear cell renal carcinoma (mnccRCC) The incidence of non-clear cell renal carcinoma (nccRCC) is low.
Compared with ccRCC, there are fewer clinical trials, and the systemic treatment regimen recommended by the guidelines is relatively single
.

The response rate of nccRCC to TKIs and mTORs is lower than that of ccRCC
.

Genetic testing of mnccRCC can help in drug selection and provide more effective treatment options
.

3.
Hereditary kidney cancer Hereditary kidney cancer accounts for about 5%-8% of kidney cancer
.

The "CSCO Kidney Cancer Diagnosis and Treatment Guidelines 2020" proposes that genetic testing is recommended for patients with onset age ≤45 years old and with bilateral, multifocal renal disease and a family history of renal cancer
.

At present, a series of pathogenic genes of hereditary renal cancer syndrome have been identified, such as VHL, MET, SDHB, FH, FLCN, PTEN, BAP1,
etc.

Genetic testing can clarify the pathological type of such patients, guide appropriate treatment, and combine genetic counseling to assess the risk of disease in immediate family members
.

4.
Bilateral or multifocal renal cancer with specific clinical features or unknown histology accounts for 5% of all renal cancers, and about 90% of multifocal renal cancers occur bilaterally at the same time, usually accompanied by more Higher probability of recurrence and worse prognosis
.

In general, this type of renal cancer is associated with genetic susceptibility, but some patients still have a later age of onset or lack a significant family history
.

Therefore, genetic testing is recommended to identify the type of gene mutation in this type of kidney cancer
.

In clinical treatment, there are still some renal cancers whose pathological types cannot be determined by the commonly used HE staining and immunohistochemistry.
The diagnosis of such renal cancers depends on the detection at the gene level, such as Xp11.
2 translocation/TFE3 gene fusion renal cell carcinoma The histological phenotype lacks typical features and requires fluorescence in situ hybridization (FISH) or TFE fusion gene testing to confirm the diagnosis
.

The content of genetic testing can be based on different testing objects and clinical needs, and different NGS sequencing technologies can be selected.
For the following known targeted therapy or immunotherapy-related gene testing (Table 1, 2), due to limited genes, it is recommended to use panel.
Form testing to ensure cost-effective
.

Table 1 Targeted drugs that may benefit from common mutated genesTable 2 Related genes or pathways that may benefit from immunotherapy Hereditary kidney cancer-related genes Hereditary kidney cancer is often accompanied by other system manifestations, but there are also only kidney cancer manifestations It is often difficult to distinguish from sporadic renal cancer by pathology alone
.

Accurate diagnosis and identification of hereditary renal cancer is an essential part of comprehensive treatment of renal cancer
.

It is necessary to detect germline mutations by NGS technology to diagnose hereditary renal cancer (Tables 3, 4)
.

Table 3 Targeted drugs that may benefit hereditary renal cancer mutated genes Table 4 Diagnosis and treatment principles for different hereditary renal cancer Clinically significant mutated genes in other tumors NCCN guidelines only recommend renal collecting duct cancer, renal medullary cancer and Sarcomatoid differentiated renal cancer can be considered for chemotherapy
.

At present, there is no guideline recommendation for the treatment of these three types of renal cancer.
The detection of chemotherapy sensitivity and toxicity prediction genes supported by evidence-based medical evidence in other tumors has certain reference significance for the selection of treatment options
.

The value of genetic testing in renal cancer prognosis In recent years, a series of retrospective studies have found the correlation between BAP1, PBRM1, SETD2, KDM5C, TP53 and TERT and renal cancer prognosis
.

BAP1, PBRM1, and TP53 have independent predictive value in advanced renal cancer patients treated with first-line TKIs
.

The updated MSKCC gene model added BAP1/TP53 and PBRM1 as independent predictors and added four risk classifications.
The MSKCC gene model made a difference in overall survival (OS) and progression-free survival (PFS) in patients with advanced renal cancer more accurate predictions
.

Table 5.
The recurrence prediction of localized renal cancer in MSKCC gene model is also a hot spot of current research.
The 6SNP molecular prediction model constructed based on gene detection single nucleotide polymorphism (SNP) has achieved reliable prediction effect (Table 6)
.

With the extensive clinical application of NGS testing, these gene models have good prospects for clinical application
.

Table 6 Recommendations of the 6SNP Molecular Prediction Model Expert Group The detection is to identify the gene mutation site, confirm the diagnosis, and provide a reference for the choice of treatment plan; for the first-line targeted therapy of advanced clear cell renal cell carcinoma with a clear diagnosis, genetic testing is not a necessary requirement
.

2.
In late ccRCC that has progressed after first-line therapy, genetic testing can assess the sensitivity of patients to targeted drugs, thereby assisting in drug decision-making for second-line and later-line therapy
.

For nccRCC, genetic testing can help select appropriate first-line therapy
.

3.
It is recommended to use blood as the germline mutation sample and tumor tissue (fresh tissue or paraffin block tissue) as the systemic mutation sample, and the process must meet the standard specifications
.

4.
The efficacy prediction markers of immunotherapy are one of the current research hotspots
.

In renal cancer, the predictive value of TMB, MSI and PBRM1 mutations remains to be clarified, and DDR pathway-related genes are predictive markers found in current clinical studies
.

Relevant gene mutations can be used as a reference factor for recommending immunotherapy, but not as a decisive factor in choosing immunotherapy
.

For patients at risk for hyperprogression who require immunotherapy, genetic testing is recommended to avoid risk
.

5.
When the tissue sample for the first genetic test is insufficient or the tissue test fails, liquid biopsy test products approved by NMPA or FDA can be used as an auxiliary or supplement
.

6.
For renal cancer patients who have not received targeted/immune drug therapy, tissue samples that have been pathologically evaluated should be the first choice for NGS testing
.

For patients who have received targeted/immunotherapy, post-treatment samples should be used whenever possible
.

7.
When conditions permit, if the patient is willing to obtain comprehensive genetic variation information, and patients with advanced new or postoperative recurrence of renal cancer, it is recommended to use NMPA or FDA-approved large-panel comprehensive genomic NGS detection products.
Develop first-line treatment regimens on the basis of tumor genomes
.

8.
Pay attention to the cooperation between urologists and oncologists, pathologists, molecular biology and bioinformatics experts, and build a new multidisciplinary diagnosis and treatment model of the molecular tumor expert committee/MDT will be an important development in the clinical and research of urological tumors direction
.

References: He Dalin, Xue Wei, Zhou Fangjian, Zhai Wei, Chen Tianyi, Dong Pei, Wu Kaijie, Guo Jianming, Li Jing, Li Lei, Luo Junhang, Niu Yuanjie, Wang Hang, Wang Wei, Xu Tao, Xu Wanhai, Zeng Hao, Zheng Junhua.
Renal cancer gene Detection of Chinese expert consensus (2021 edition) [J].
Journal of Modern Urology, 2022, 27(03): 192-200.
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