Double Hit in Clear-Cell Renal Cell Carcinoma With Germline Pathogenic ATM Mutation and Somatic VHL Mutation

Introduction

In 2024, an estimated 81,610 Americans will be diagnosed with cancers of the kidney and renal pelvis, and 14,390 will die of the disease. ¹ Established risk factors for the development of renal cell carcinoma (RCC) include smoking, ² obesity, ³ and hypertension. ⁴ While relatively uncommon, accounting for only around 3% of RCC cases, hereditary forms do exist. ⁵ NCCN guidelines identify 7 major hereditary syndromes linked to an elevated RCC risk: BAP1 tumor predisposition syndrome (BAP1-TPDS), Birt-Hogg-Dubé syndrome (BHDS), hereditary leiomyomatosis and renal cell carcinoma (HLRCC, FH-deficient), hereditary papillary renal carcinoma (HPRC), hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndrome (SDH-deficient), tuberous sclerosis complex (TSC), and von Hippel-Lindau (VHL) disease. ⁶

Inherited mutations in genes essential for DNA repair, including ataxia-telangiectasia mutated (ATM), breast cancer (BRCA), and TP53, significantly increase the risk of developing various cancers. ⁷ Biallelic pathogenic mutations in ATM can cause ataxia-telangiectasia (A-T) syndrome, a disorder characterized by neurodegeneration, telangiectasia, immune system deficiencies, a predisposition to various cancers, and heightened radiosensitivity.8 While A-T is rare, with a global prevalence estimated between 1 in 40,000 and 1 in 100,000 live births, heterozygous germline mutations in the ATM gene occur in approximately 1% of the population and also increase cancer risk. ⁸

Traditionally, RCC has not been linked to germline pathogenic mutations in the ATM gene. Germline ATM mutations have only been identified in a small cohort of patients in multiple retrospective analyses.^{9 -11} However, there is limited information on the role of somatic mutations in addition to germline ATM mutations in predisposing individuals to RCC development. Here, we describe a novel case highlighting the double-hit phenomenon in a patient with germline pathogenic ATM mutations and a significant family history of cancers, who developed a somatic mutation of VHL and subsequently RCC at a young age. This case report aims to emphasize the importance of screening for RCC in patients with germline pathogenic ATM mutations, suggesting that screening should not be limited to breast, gastrointestinal, and prostate cancers.

Case Presentation

A 68-year-old woman with a medical history significant for hypertension, dyslipidemia, hypothyroidism, and Barrett’s esophagitis initially presented to the hospital in September 2023 for gross hematuria and urinary retention. A CT scan of the abdomen and pelvis on September 20, 2023, revealed a 6 × 7 × 5 cm complex mass in the superior pole of the right kidney, suggestive of malignancy (Figure 1), and a 3-cm cyst in the pancreatic tail. The patient underwent an EGD/EUS with fine needle aspiration and biopsy, which also revealed a gallbladder polyp measuring 1×9 cm. Cytopathology of the pancreatic cyst was negative for malignancy.

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Figure 1.

A CT scan of the abdomen and pelvis revealed a 6 × 7 × 5 cm complex mass in the superior pole of the right kidney, suggestive of malignancy.

Notably, the patient has an extensive family history of cancer. Her mother was diagnosed with colorectal cancer at age 40, and her father was diagnosed with an unknown cancer at age 45. In 2022, her brother was diagnosed with prostate cancer and subsequently found to have metastatic pancreatic cancer. This led to germline testing, which revealed that her brother had an ATM gene mutation (ATM c.8786+1G>A heterozygous mutation). Subsequently, the patient also tested positive for this germline mutation.

Given the germline ATM gene mutation and extensive family history of malignancy, the patient was followed by a gastroenterologist for the pancreatic tail cyst and renal mass. In November 2023, she underwent robotic-assisted laparoscopic right radical nephrectomy (Figure 2), distal pancreatectomy, and cholecystectomy. Pathology revealed high-risk clear cell RCC, pT2a, histology grade 3 with rhabdoid features (Figure 3), measuring about 8.4 cm, with no regional lymph node metastasis. The distal pancreas pathology showed a serous cystadenoma of the pancreas, measuring 3.1 cm, in the background with focal low-grade pancreatic intraepithelial neoplasia (PanIN) and islet cell hyperplasia/pseudohyperplasia. Twelve lymph nodes were negative for tumors (0/12). Gallbladder pathology showed chronic cholecystitis and cystic adenomyoma.

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Figure 2.

Gross specimen after robotic-assisted laparoscopic right radical nephrectomy.

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Figure 3.

Pathology slides revealed high-risk clear cell RCC, histology grade 3 with rhabdoid features.

The patient was subsequently referred to the oncology clinic for a discussion about adjuvant treatment due to the high-grade, rhabdoid clear cell RCC. Tempus somatic mutation testing revealed an acquired VHL somatic mutation (p.L101fs Frameshift loss of function mutation, variant allele frequency [VAF] 20.8%) in addition to the germline pathogenic ATM c.8786+1 G>A splice region variant loss of function mutation (VAF 47.9%) (Figure 2). The patient likely has a double-hit phenomenon with a germline ATM and a somatic VHL mutation, leading to the development of aggressive high-risk RCC.

The patient was started on adjuvant pembrolizumab with anticipation for 1 year. She continues to undergo regular cancer screenings, including alternating mammogram and breast magnetic resonance imaging (MRI) every 6 months for breast cancer and MRI pancreatic protocol and EGD/EUS for pancreatic cancer.

Discussion

Inherited mutations in essential DNA repair genes, such as ATM, BRCA, and TP53, significantly increase the risk of developing various cancers.7 The ATM gene, located on chromosome 11q22–23, is one of the largest genes in the genome, comprising 66 exons with a coding sequence spanning 9,168 base pairs. As a tumor suppressor, ATM encodes a PI3K-related serine/threonine protein kinase crucial for recognizing DNA damage and preserving genomic integrity. ¹² Biallelic mutations in ATM cause A-T syndrome, which is characterized by neurodegeneration, telangiectasia, immune deficiencies, cancer predisposition, and heightened radiosensitivity. A-T is rare, however, heterozygous germline ATM mutations, found in about 1% of the population, also increase cancer risk. ⁸

A retrospective cohort study that sought to estimate cancer risks associated with ATM pathogenic variants while considering familial history revealed significant risks for pancreatic (OR 4.21), prostate (OR 2.58), gastric (OR 2.97), and invasive ductal breast cancers (OR 2.03). The c.7271T>G variant showed a higher risk for invasive ductal breast cancer (OR 3.76). In addition, moderate risks were noted for ductal carcinoma in situ (OR 1.80), male breast cancer (OR 1.72), ovarian cancer (OR 1.57), colorectal cancer (OR 1.49), and melanoma (OR 1.46). ¹³

The relationship between germline ATM mutations and RCC is largely unexplored. In a retrospective analysis of 206 genitourinary cancer patients with germline mutations, ATM mutations were prevalent, yet mutations in GJB2, MET, MUTYH, and VHL were more commonly associated with kidney malignancies.9 Another analysis of 322 Chinese RCC patients found germline variants in about 10%, with only 0.6% having ATM mutations.10 Similarly, in a cohort of 55 Chinese RCC patients, the germline mutation rate was 12.7%, with only 1 ATM mutation identified. ¹¹

The Knudson 2-hit hypothesis, proposed by Alfred Knudson in 1971, explains how mutations in tumor suppressor genes lead to cancer development.14 It suggests that 2 genetic “hits” are required: an inherited germline mutation and a somatic mutation occurring in a specific cell during the individual’s lifetime. This second mutation inactivates the remaining normal allele, leading to unregulated cell growth and cancer. ¹⁴ Beyond the Knudson 2-hit hypothesis, which involves mutations occurring on the same gene, we observed a relatively underrecognized double-hit phenomenon in our patient. This involved a pathogenic germline mutation and an acquired somatic mutation in 2 different pathogenic genes.

In our patient, a germline ATM mutation and an acquired somatic VHL mutation likely drove RCC tumorigenesis. The absence of ATM increases genomic instability by impairing double-strand break DNA repair, forcing cancer cells to rely on alternative repair pathways.7 The VHL gene, a tumor suppressor on chromosome 3p25, regulates cell growth and angiogenesis. The protein encoded by the VHL gene is the substrate recognition component of a protein complex that involved in the ubiquitination and subsequent degradation of hypoxia-inducible factors (HIFs).^15,16 Mutations in VHL disrupt this pathway, causing uncontrolled cell proliferation and angiogenesis.^15,16

There is limited literature on the association between ATM and RCC. Current guidelines, including those from the NCCN, do not include RCC screening for patients with germline ATM mutations. We highlight the risk of RCC in these patients, especially when they acquire somatic mutations with the double-hit phenomenon. Increased awareness and screening for RCC are essential for patients presenting with hematuria, urinary retention, and renal lesions.

Novel targeted therapies have been developed for VHL and ATM pathways. However, treatments for patients with both germline and somatic mutations that drive tumorigenesis through 2 mechanisms are not well described. Combining targeted treatments for VHL (e.g., the HIF2α inhibitor belzutifan) and ATM pathways (e.g., PARP inhibitors) may be necessary in advanced stage or recurrent cancer.

Clinical trials focused on combined targeted treatments are essential to improve outcomes for patients with similar genetic profiles. This case emphasizes the critical role of genetic screening and personalized treatment strategies in managing hereditary cancer syndromes.

Conclusion

This case report underscores the significance of considering RCC in patients with pathogenic germline ATM mutations, a connection that is traditionally overlooked. Our patient, who has both a pathogenic germline ATM mutation and a somatic VHL mutation, illustrates a possible application of the double hit, highlighting the potential for aggressive RCC development through combined genetic alterations. The limited literature on the association between ATM mutations and RCC calls for heightened awareness among health care providers. Our findings advocate for incorporating RCC screening in patients with germline ATM mutations, particularly when they present with renal-related symptoms such as hematuria or urinary retention. Furthermore, the interplay between germline and somatic mutations in tumorigenesis warrants additional research to refine screening protocols and develop targeted therapies.