Pancreatic Adenocarcinoma Associated With a Germline RAD51C Mutation

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality in the United States, with a 5-year survival of ∼10%–13%. Although 5%–10% of PDAC cases arise from pathogenic germline variants in cancer-predisposition genes, association with RAD51C remains exceedingly rare, with only one prior case reported. We describe a 64-year-old woman who presented with progressive epigastric pain and was found to have a hypermetabolic pancreatic head mass with markedly elevated CA 19-9. Endoscopic biopsy confirmed pancreatic adenocarcinoma (MSI-stable, HER2-negative), staged as cT2N0M0. Comprehensive germline testing identified a pathogenic RAD51C mutation. The patient declined treatment and genetic counseling, electing for palliative care. RAD51C plays a critical role in homologous recombination DNA repair, and its loss may confer sensitivity to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors. This case represents only the second reported RAD51C-associated PDAC and reinforces the importance of universal germline testing to identify hereditary risk and guide therapeutic strategies.

INTRODUCTION

Pancreatic adenocarcinoma is a highly lethal cancer, and it is the third leading cause of cancer-related mortality. Approximately 5%–10% of pancreatic cancers are caused by inherited pathogenic genetic mutations (germline variants) in cancer predisposition genes. The most commonly implicated genes are BRCA1, BRCA2, ATM, PALB2, CDKN2A, STK11, TP53, and mismatch repair genes associated with Lynch syndrome.¹

RAD51C is an essential gene within the homologous recombination DNA repair (HRR) pathway, playing a central role in preserving genomic integrity. Pathogenic loss-of-function variants in RAD51C are well-recognized contributors to hereditary breast and ovarian cancer syndromes and have also been implicated in Fanconi anemia. However, the association of RAD51C with pancreatic cancer is rare and is only now being recognized.

Although RAD51C variants have been identified in large PDAC cohorts, clinically detailed case reports describing RAD51C-associated PDAC remain exceedingly rare, with only 1 prior documented case.²

CASE REPORT

A 64-year-old woman with a history of diabetes, hyperlipidemia, and systemic sarcoidosis on infliximab presented with 4 weeks of persistent epigastric pain. Her pain, initially episodic, had become constant. Physical examination was unremarkable except for mild epigastric tenderness. Laboratory evaluation revealed normal complete blood count, mildly elevated lipase, and elevated inflammatory markers (erythrocryte sedimentation rate and C-reactive protein).

Computed tomography (CT) abdomen demonstrated a mixed cystic and solid mass at the junction of the pancreatic head and body, dilatation of the pancreatic duct, and multiple hepatic and splenic lesions consistent with previously known sarcoidosis (Figure 1). No evidence of pancreatitis was noted. Positron emission tomography/CT (PET/CT) showed an intensely hypermetabolic 37-mm lesion in the pancreatic head without additional foci of malignancy.

Figure 1.

Pancreatic head mass fine needle aspiration showing infiltrating pancreatic ductal carcinoma on H&E stain at 20× magnification (red arrow).

Endoscopic ultrasound-guided fine needle biopsy confirmed pancreatic adenocarcinoma (MSI stable, HER2 negative) (Figure 2). Serum CA 19-9 was markedly elevated at 58,277 U/mL. Surgical oncology evaluation staged the tumor as cT2N0M0 (Stage IB).

Figure 2.

CT abdomen showing mixed solid-cystic mass in the pancreas (red arrow).

Genetic testing (Fulgent hereditary cancer panel) identified a RAD51C variant: (c.914G>A; p.Trp305*), heterozygous, classified as likely pathogenic per American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria, conferring increased risk for breast and ovarian cancers. Oncology recommended neoadjuvant FOLFIRINOX chemotherapy for 6 months followed by surgical reassessment. Despite extensive counseling, the patient declined chemotherapy and surgery, electing to pursue palliative care. She also declined genetic counseling despite being informed of familial implications. The patient passed away 4 months after diagnosis.

DISCUSSION

RAD51C is a key member of the RAD51 paralog complexes, which are essential for the maintenance of genomic stability. These complexes participate in homologous recombination mediated repair of double-strand DNA breaks, resolution of Holliday junction intermediates, and stabilization of stalled replication forks during replication stress. Pathogenic variants in RAD51C are well established in hereditary breast and ovarian cancer syndromes, and biallelic loss has been associated with Fanconi anemia–like phenotypes.³

Although RAD51C mutations have been documented in multiple large-scale PDAC cohorts with frequency ranging between 0.3 and 0.6%,^4,5 there is still insufficient evidence to support a clear association between RAD51C and pancreatic cancer risk. Unlike BRCA2, ATM, CDKN2A, and STK11, RAD51C is not included in NCCN pancreatic cancer screening recommendations. Emerging data suggest that HRR gene mutation carriers, including RAD51C, present at younger ages with more advanced disease yet demonstrate significantly improved overall survival (homologous recombination 0.83, P = 0.02), potentially related to enhanced platinum sensitivity.⁶

Genetic testing identified a nonsense variant RAD51C variant: (c.914G>A; p.Trp305*), heterozygous, classified as likely pathogenic per ACMG/AMP criteria. This protein-truncating variant has been well established as pathogenic in hereditary breast and ovarian cancer syndromes.

Pancreatic ductal adenocarcinoma is an aggressive malignancy with rising incidence and persistently poor outcomes. The overall 5-year survival remains approximately 10%–13%, underscoring the importance of identifying individuals with inherited susceptibility who may benefit from early detection strategies. Germline testing plays a critical role in this effort. Recent updates from the American Society of Clinical Oncology and the National Comprehensive Cancer Network (NCCN) recommend universal germline testing for all patients diagnosed with PDAC, regardless of age, personal cancer history, family history, or ethnicity.⁷

Therapeutically, detecting defects in HRR genes has meaningful implications for treatment selection in PDAC. Mutations in HRR genes such as BRCA1, BRCA2, and PALB2 confer increased sensitivity to platinum-based chemotherapy and may qualify patients for maintenance therapy with PARP inhibitors. Although data specific to RAD51C are limited, RAD51C functions within the same HRR pathway and may, therefore, show good response to platinum-based therapy. The only other clinically reported RAD51C mutation associated PDAC case showed an exceptional response to FOLRINOX, with prolonged survival exceeding 3 years.⁸ This underscores the importance of early identification of HRR mutations to inform therapeutic decision making.

A significant limitation of this case is that the patient declined treatment and genetic counselling. This represents a dual missed opportunity: potential platinum sensitivity and improved outcomes with FOLFIRINOX were not pursued, and first-degree relatives remain unaware of their 50% risk of inheriting the RAD51C mutation with its associated 10%–15% lifetime ovarian cancer risk and ∼20% breast cancer risk that warrant specific screening and risk-reduction interventions. Her survival of 4 months from diagnosis is substantially shorter than the reported outcomes for patients with HRR-mutated PDAC receiving platinum-based therapy, underscoring the critical importance of treatment acceptance. This case emphasizes that although genetic testing identifies actionable mutations, clinical benefit requires patient engagement with recommended therapies.

We report a rare case of pancreatic adenocarcinoma associated with the RAD51C germline mutation, representing only the second such clinically detailed case report. This finding emphasizes the significance of universal germline testing in pancreatic cancer, the potential therapeutic relevance of homologous recombination deficiency, and the importance of genetic counseling for patients and their families. Additional research is needed to better define the role of RAD51C in pancreatic tumorigenesis and its implications for targeted therapies.

DISCLOSURES

Author contributions A. Lawrence: conception, data collection, drafting of the manuscript. I. Villanueva: histopathologic analysis. J. Parikh: supervision, critical manuscript revision. A. Mandalia: literature review, clinical data analysis, critical manuscript revision, final manuscript review, and approval. A. Lawrence is the article guarantor.

Financial disclosure: None to report.

Informed consent was obtained for this case report.

This material is the result of work supported with resources and the use of facilities at the Orlando VA Healthcare System (Orlando, FL). The contents of this publication do not represent the views of the Department of Veterans Affairs or the United States Government.

ABBREVIATIONS:

ACMG/AMP

American College of Medical Genetics and Genomics/Association for Molecular Pathology

ASCO

American Society of Clinical Oncology

CA- 19-9

carbohydrate antigen 19-9

CRP

C-reactive protein

CT

computed tomography

ESR

erythrocyte sedimentation rate

FOLFIRINOX

combination chemotherapy regimen (folinic acid, fluorouracil, irinotecan, and oxaliplatin)

HER2

human epidermal growth factor receptor 2

HR

homologous recombination

HRR

homologous recombination repair

MSI

microsatellite instability

NCCN

National Comprehensive Cancer Network

PARP

poly (ADP-ribose) polymerase

PDAC

pancreatic ductal adenocarcinoma

PET/CT

positron emission tomography/computed tomography

RAD51C

RAD51 paralog C (DNA repair gene)