Prevalence of germline mutations in cancer susceptibility genes in Chinese patients with renal cell carcinoma

Introduction

Renal cell carcinoma (RCC) is the ninth most frequently diagnosed cancer in men (1). RCC comprises several subtypes, including clear cell RCC (ccRCC), papillary RCC type 1 (pRCC T1), pRCC T2, mixed oncocytoma or chromophobe RCC (chRCC), and other rare subtypes (2). Tumors that do not meet the criteria for any established subtype are categorized as unclassified (3). Loss of function of the von Hippel-Lindau (VHL) protein, mutations in MET, FH, and FLCN have been considered major mutations in ccRCC, pRCC T1, and pRCC T2, and mixed oncocytoma or chRCC, respectively (2). Germline mutations, one of genetic alterations, exist in all cells in body and can be inherited (4,5). Germline mutations are associated with generation of various tumors and drug resistance (6-8). A recent American study found that 16.1% of RCC patients carried germline mutations in a RCC predisposition gene, and some cases of early-onset aggressive RCC without defined pathogenic germline mutations have been observed (9). It seems highly probable that underlying causative germline mutations exist in RCC. Thus, further investigations need to be explored in different patient populations with special molecular and clinical characteristics.

A previous report suggested that patients with renal cancer affected by hereditary factors account for 3–5% of all RCC patients (10), which is likely underestimated (11). Studies have shown that germline mutations in 14 genes (VHL, FH, SDHB, SDHC, SDHD, MET, FLCN, PTEN, TSC1, TSC2, MITF, BAP1, PBRM1, and CDKN2B) can increase the risk of RCC (12-15). It is particularly relevant to identify Chinese patients with inherited RCC because their clinical implications can differ from those of patients with sporadic RCC (16,17). However, the genetic basis of some inherited renal cancers has not been clearly elucidated.

To explore the genetic basis of inherited renal cancers, we conducted a comprehensive germline analysis of multiple renal cancer predisposition genes in a cohort of Chinese patients. Among the patients in our cohort, 10.57% carried pathogenic/likely pathogenic germline mutations. Most (6/10) of the mutated genes were associated with maintenance of genomic stability and DNA repair. Young RCC patients, patients with bilateral or multifocal RCC, or patients with non-clear cell RCC (nccRCC) are more likely to have pathogenic/likely pathogenic germline mutations. Importantly, this is the first study to report that identical germline mutations of the FANCI gene c.158-2A>G and FANCM gene c.4515+1G>C exist in patients with RCC and is the first article to show heterozygous germline missense mutation in exon 5 of the FH gene c.563A>T:p.N188I in RCC. We present the following article in accordance with the MDAR reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-23-32/rc).

Methods

Patients

Peripheral blood was obtained from 123 patients with RCC in the Department of Urology, The Third Medical Center, Chinese PLA General Hospital between 1 August 2017 and 31 December 2020. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Chinese PLA General Hospital (No. S2013-065-01) and informed consent was taken from all the patients.

Genomic sequencing

In our cohort, whole-exome sequencing (WES) (n=69) or gene panel sequencing containing 139 genes (n=54) related to germline cancer predisposition was performed to evaluate the pathogenic/likely pathogenic germline mutation rate and identify de novo pathogenic/likely pathogenic germline mutations in patients with RCC (Table S1). Germline DNA was obtained from peripheral white blood. Polymerase chain reaction (PCR) was performed to amplify DNA. The enriched DNA, which was converted to sequencing libraries, was sequenced and analyzed using the Illumina Novoseq platform (Illumina, San Diego, CA, USA), as previously described (18).

Statistics

Clinical and pathologic characteristics were compared using chi-square test (χ²) and P values <0.05 were considered significant. Statistical analyses were performed using SPSS 24.0 software (IBM Corp., Armonk, NY, USA).

Results

Patient characteristics

The characteristics and clinical features of the 123 patients are summarized in Table 1. In our study, the age at diagnosis varied from 19 to 85 years (median, 54 years). Among the 123 patients, 95 had ccRCC (77.2%) and 28 had nccRCC (22.8%). Overall, 7 patients (5.7%) with a history of a second malignant tumor were identified. Of the 7 patients with secondary malignant tumors, 2 were diagnosed with breast cancer (data not shown). A total of 16 (13.0%) patients with bilateral or multifocal disease were reported and only 2 (1.6%) patients had a family history of RCC (data not shown).

Germline mutations

A total of 13 patients (10.6%) harbored pathogenic or likely pathogenic germline variants in 10 different cancer predisposition genes (Figure 1A). Mutations in RCC-associated genes were identified in 9 (7.3%) patients, and mutations in genes not clearly associated with RCC were identified in 6 (4.9%) patients (Figure 1B). A total of 6 of 95 (6.3%) ccRCC patients had pathogenic/likely pathogenic germline mutations, and 7 of 28 (25.0%) nccRCC patients had pathogenic/likely pathogenic germline mutations (Figure 1C, Table 2). Among the 95 ccRCC patients, 4 (4.2%) patients harbored pathogenic/likely pathogenic germline mutations in RCC-associated genes (Figure 1D). Among the 28 patients with nccRCC, 5 (17.9%) harbored pathogenic/likely pathogenic germline mutations in RCC-associated genes (Figure 1D). For RCC-associated genes (Figure 1B, Table S2), 4 deleterious VHL mutations were detected in 4 individuals (3.3%), including 75.0% (n=3) known deleterious missense mutations and 25.0% (n=1) nonsense mutations. We detected 2 deleterious FLCN mutations in 2 participants (1.6%), including 1 frameshift in/del mutation and 1 deleterious missense mutation. We detected 2 deleterious FH mutations in 2 participants (1.6%), both of which were deleterious missense mutations. We also found 1 SDHB deleterious missense mutation in 1 participant (0.8%). For other cancer-associated genes (Figure 1B, Table S2), 1 MUTYH deleterious missense mutation, 1 RAD51C deleterious missense mutation, 1 NBN likely pathogenic missense mutation, 1 RAD50 frameshift mutation, 1 FANCI deleterious missense mutation, and 1 FANCM deleterious missense mutation were identified. The VHL, FH, FLCN, SDHB, MUTYH, NBN, and RAD51C pathogenic or likely pathogenic mutations in RCC have been reported before, whereas the FANCI and FANCM pathogenic germline mutations in RCC were reported for the first time in this study. Interestingly, 2 patients in our cohort had simultaneous occurrences of 2 causative mutations (Table S2). Patients harboring VHL and FANCM mutations (nonsense and missense, respectively) simultaneously experienced stage I ccRCC at 29 years of age, without a family history of malignant diseases. Similar characteristics were observed in a patient harboring VHL and RAD51C mutations (deletions and missense mutations, respectively). He was diagnosed with stage I ccRCC at 44 years of age, with a family history of malignant cancers. Compared with the phenotypes of patients with only 1 mutation in VHL, no apparent phenotypic differences were found between these 2 patients. The only difference was that patients with only VHL mutations had a single lesion, whereas the patients with both VHL and FANCM/RAD51C mutations had multifocal RCC. In these 2 cases, it seemed that additional FANCM or RAD51C mutations did not affect the age of RCC onset. Thus, to draw a decisive conclusion, further investigations are required to demonstrate the precise role of FANCM and RAD51C in tumorigenesis and tumor progression of RCC.

Figure 1 Frequency of germline variants in the cohort of 123 patients with RCC. (A) Percentage of patients with germline variants in RCC predisposition genes including VHL, FH, FLCN, SDHB, MUTYH, RAD51C, NBN, RAD50, FANCI, and FANCM. One patient harbored VHL and FANCM mutations simultaneously, and another patient harbored VHL and RAD51C mutations simultaneously. (B) Number of pathogenic mutations by histologic subtype. (C,D) Percentage of germline mutations in ccRCC and nccRCC. ccRCC, clear cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma; RCC, renal cell carcinoma.

Clinical characteristics associated with germline mutations

Our cohort comprised 6 patients with ccRCC, 2 patients with pRCC, 2 with chRCC, 1 with microphthalmia (MiT) family translocation RCC, and 2 with unclassified RCC who carried pathogenic/likely pathogenic germline mutations (Figure 2, Table S2). The proposed renal cancer predisposition gene FH pathogenic germline mutations were identified in the 2 patients with pRCC. There were 2 patients with chRCC who harbored mutations in either FLCN or SDHB. The mean age of onset of RCC in germline mutation carriers was 37.2 years. Of these 13 patients, 2 (15.4%) experienced metastasis. A positive family history of cancer was reported in 6 patients (Table S2). The prevalence of deleterious germline mutations is associated with the age at diagnosis. The probability of germline mutations occurring in patients aged 46 years or younger remained higher than that in patients older than 46 years [11 (26.8%) of 41 vs. 2 (2.4%) of 82, P<0.001] (Table 2). We also found that the prevalence of germline mutations was associated with the histologic subtype. Patients with nccRCC were more likely to carry germline mutations [7 (25%) of 28 vs. 6 (6.3%) of 95, P=0.005] (Figure 1C, Table 2). Furthermore, we also found that patients with nccRCC were more likely to have RCC-associated gene mutations [5 (17.9%) of 28 vs. 4 (4.2%) of 95, P=0.015] (Figure 1D). Compared to patients without bilateral or multifocal RCC, those with bilateral or multifocal RCC were more likely to harbor deleterious mutations [5 (38.5%) of 13 vs. 11 (10.0%) of 110, P=0.004] (Table 2). However, a family history of cancer was not associated with more mutations (Table 2). Additionally, a higher stage or grade was not associated with more deleterious pathogenic germline mutations in our study.

Figure 2 Number of pathogenic mutations by disease. RCC, renal cell carcinoma.

Genes involved in the maintenance of genomic stability or DNA repair were frequently mutated

In our cohort, 13 (13/123, 10.6%) patients harbored deleterious germline mutations in cancer predisposition genes. Some 6 of 10 cancer predisposition genes were associated with maintenance of genomic stability and DNA repair (Figure 3). Deleterious germline mutations of 3 Fanconi anemia (FA)-related genes (FANCI, FANCM, and RAD51C) were detected. The protein products of these genes function cooperatively with other proteins associated with DNA repair processes to maintain genome homeostasis, and loss of function of these genes leads to FA (19). In addition, deleterious germline mutations in RAD50 and NBN have been detected: RAD50 and NBN, members of the MRE11/RAD50/NBN double-strand break repair complex, are thought to repair DNA double-strand breaks and activate DNA damage-induced checkpoints (20,21). Loss of function of these genes is associated with rare chromosomal instability disorders (20,21). Additionally, a deleterious germline mutation in MUTYH was detected. MUTYH, a gene encoding a DNA glycosylase, plays an important role in oxidative DNA damage repair. Inactivation of MUTYH leads to G:C>T:A transversion, which increases the risk of colorectal cancer (22).

Figure 3 Percentage of genes associated with genomic stability or DNA repair.

Novel pathogenic germline mutation in RCC

In this study, FANCI and FANCM pathogenic/likely pathogenic germline mutations in patients with RCC were reported for the first time. Patient RCC88 diagnosed with ccRCC carried a FANCM germline mutation annotated as pathogenic in ClinVar (23). This revealed a heterozygous NM_020937:c.4515+1G>C germline FANCM missense mutation, resulting in inactivation of FANCM (Table S3). This intronic variant is a nucleotide substitution located 1 nucleotide downstream of coding exon 17. Interestingly, patient RCC88 simultaneously harbored a pathogenic VHL germline mutation. Subsequent Sanger sequencing of DNA samples collected from the blood of patient RCC88 confirmed the presence of FANCM and VHL germline mutations (Figure 4A,4B). Interestingly, genetic testing of DNA samples collected from the proband’s parents and brother revealed that none of them were carriers of FANCM or VHL mutations (Figure S1), suggesting that the de novo germline mutation occurs during formation of the sperm or egg from an unaffected parent. In addition, patient RCC88 did not have a family history of cancer. Patient RCC63, diagnosed with unclarified RCC, carried a heterozygous NM_001113378: c.158-2A>G germline FANCI missense mutation, which is predicted to inactivate the FANCI gene (Table S3). This intronic variant is a nucleotide substitution located 2 nucleotides upstream of coding exon 4. Subsequent Sanger sequencing of DNA samples collected from the blood of patient RCC63 confirmed FANCI germline mutations (Figure 4C). Annotated as pathogenic in ClinVar, the FANCI variant was considered pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria (24). The patient’s father was diagnosed with gastric cancer. In addition, we report a case of aggressive hereditary leiomyomatosis and RCC (HLRCC) in a 32-year-old woman who presented with a novel heterozygous germline missense mutation in exon 5 of FH (c.563A>T:p.N188I) (Figure 4D, Table S3). The patient’s mother was diagnosed with endometrial carcinoma. Consistent with a recent study, we also found a pathogenic RAD50 germline mutation (c.2165dupA; p.E723fs) in a 24-year-old RCC patient with no family history of cancer (Figure 4E, Table S3) (25).

Figure 4 Variants of FANCM, VHL, FANCI, FH, and RAD50 in patients with RCC. Sanger sequencing chromatograms for FANCM-positive, VHL-positive, FANCI-positive, FH-positive, and RAD50-positive cases. Genetic testing of peripheral blood collected from patient RCC88 identified (A) a FANCM germline mutation (c.4515+1G>C) and (B) a VHL germline mutation (c.264G>A; p.W88*). Genetic testing of peripheral blood collected from patient RCC63, RCC121, and RCC93 identified (C) a FANCI germline mutation (c.158-2A>G), (D) an FH germline mutation (c.563A>T:p.N188I), and (E) a RAD50 germline mutation (c.2165dupA; p. E723fs), respectively. RCC, renal cell carcinoma.

Discussion

Patients with renal cancer affected by hereditary factors account for 3–5% of all RCC patients. Pathogenic germline mutations in cancer predisposition genes are associated with tumorigenesis and development of RCC (26). VHL disease is an autosomal dominant disorder caused by germline mutations in the VHL gene. Patients with VHL disease are particularly prone to renal tumors when a stochastic secondary inactivation of the other VHL allele occurs (27). Similar to those with VHL disease, patients with TSC1/2, FH and SDHB/C/D germline mutations are more likely to have RCC (28-30). Germline mutation in MET can promote hereditary pRCC initiation and progression (31,32). The identification of RCC patients with certain pathogenic germline mutations has important clinical implications, guiding systemic therapy and clinical trial eligibility (16,17,33). Although most studies have investigated the prevalence of germline mutations among patients with RCC and some cancer-predisposition genes involved in the tumorigenesis and tumor progression of RCC have been identified (9,25,34), the genetic basis of some inherited renal cancers has not been clearly elucidated. Here, we conducted a study using WES or gene panel sequencing of 139 genes to evaluate the pathogenic/likely pathogenic germline mutation rate and identify de novo pathogenic/likely pathogenic germline mutations in patients with RCC.

Patients with nccRCC or multifocal RCC, multifocal disease at diagnosis, are at higher risk for inherited syndromes and are significantly more likely to have pathogenic germline mutations (9). Similarly, we showed that patients with bilateral or multifocal nccRCC are more likely to have pathogenic/likely pathogenic germline mutations. Early-onset cancer is a hallmark of an inherited cancer predisposition (35,36), and studies have shown that patients with mutations in RCC-associated genes, such as VHL, FH, FLCN, and SDHB, are at risk for the development of early-onset RCC (37-39). Loss of function of MUTYH accounts for 3% of early-onset CRC (40,41). Mutations in MRE11-RAD50-NBS1 (MRN) complex components, FANCM, or FANCI are associated with early-onset cancers (42-44). We also found that patients with early onset are more likely to carry pathogenic mutations (Table 2). However, Carlo et al. suggested that age at diagnosis was not related to the possibility of germline mutations in patients with advanced RCC (9). These seemingly contradictory findings may be due to Carlo et al. only including patients with advanced tumor stages in their study.

Genome instability is a hallmark of cancer cells and can be accelerated by defects in cellular responses to DNA damage (45,46). In our study, we found that 6 of 10 cancer predisposition genes were associated with maintenance of genomic stability and DNA repair (Figure 3). Deleterious germline mutations of 3 FA-related genes were reported. FA is considered a genetic disease associated with a predisposition to non-hematological and hematological malignancies (47,48). The proteins encoded by these genes comprise the DNA damage response (DDR) system and play vital roles in various cellular processes. Increasing evidence suggests that the defective function of these proteins can be associated with genomic instability, increasing cancer risk (49). Thus, further studies are required to elucidate the role of each component in tumorigenesis and tumor progression in RCC. RAD50 and NBN are components of the MRN complex and are involved in the repair of DNA double-strand breaks. As one of the first sensors and responders to DNA damage, the MRN complex plays a vital role in DDR (45,50). Mutations in the MRN complex are also associated with an increased risk of cancer, suggesting that the complex functions as a tumor suppressor (51-54). However, some studies have shown that the complete knockout of any component of the murine MRN complex can impair early embryonic development (55-57), suggesting that some functions of the MRN complex must be preserved in human disease-associated alleles.

In our study, we found that 2 patients with RCC harbored FANCI and FANCM pathogenic germline mutations. To our knowledge, this is the first report of germline mutations in these pathogenic genes in RCC. As highly conserved DNA remodeling enzymes (58-60), FANCI and FANCM can activate the FA DNA repair pathway to maintain genomic stability. Patients with FA, characterized by the clinically and genetically heterogeneous syndrome of bone marrow failure, are predisposed with a predisposition to cancers (61-64). Studies have shown that the loss of function of some FA genes (such as BRCA1 and BRCA2) by germline inactivation can result in familial breast cancer predisposition syndromes (65-70). In addition, pathogenic FA germline mutations can occur in colorectal cancer, pancreatic cancer, and leukemia (71-73). As members of the FA complementation group, FANCI and FANCM play important roles in the initiation of various cancers. Wang et al. found FANCM mutation in a patient with four primary cancer including renal cancer (74). Mutations in these two genes are associated with renal ectopia malformations or dysplasia (19,75) Thus, we suspected that FANCI and FANCM pathogenic germline mutations might play an important role in tumorigenesis and tumor progression in RCC and further studies are needed to confirm this hypothesis.

There were some limitations in our study. Larger cohorts will need to be studied to confirm the frequency of FANCI and FANCM pathogenic germline mutations in RCC and basic experiments are required to validate the biological role of FANCI and FANCM pathogenic germline mutations in RCC.

Conclusions

Considering our results and the evidence in the literature, the proportion of patients with RCC in our study who carried pathogenic germline mutations may be underestimated. Genetic testing of all patients with nccRCC, patients with bilateral or multifocal RCC, especially those aged 46 years or younger might help identify individual patients for whom targeted therapies are indicated. Patients with FANCI and FANCM pathogenic germline mutations may play an important role in tumorigenesis and tumor progression in RCC.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-23-32/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-23-32/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-23-32/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-32/coif). Xu Zhang serves as an unpaid editorial board member of Translational Andrology and Urology from April 2022 to March 2023. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Chinese PLA General Hospital (No. S2013-065-01) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones)