Investigating the prevalence of pathogenic variants in Saudi Arabian patients with familial cancer using a multigene next generation sequencing panel.

Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH. Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome (p = 0.026); TP53 c.868C>T; - multiple colon polyposis (p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.

Papillary Tumor of the Pineal Region Rare Pediatric CNS Tumor Case Series Treated in King Fahad Medical City (KFMC).

The clinical behaviors, prognosis, and appropriate treatments of papillary tumors of the pineal region (PTPR) are not fully defined due to the rarity of these tumors. At diagnosis, PTPR may present with clinical symptoms, including headache with obstructive hydrocephalus, diplopia, vomiting, and lethargy, as well as neurological signs, including Argyll Robertson pupils and Parinaud's syndrome due to compression of the dorsal midbrain, specifically the periaqueductal region with horizontal nystagmus. Radiological assessment of pineal region lesions is challenging, with a wide range of potential differential diagnoses. PTPR typically presents as a heterogeneous, well-circumscribed mass in the pineal region, which might contain cystic areas, calcifications, hemorrhages, or protein accumulations. Here, we report three female pediatric patients with PTPR treated in King Fahad Medical City (KFMC) in Saudi Arabia. Histological and immunohistochemical diagnosis was confirmed by analysis of genome-wide DNA methylation profiles. This case series expands on the available reports on the clinical presentations of PTPR and provides important information on the responses to different treatment modalities.

Epigenomics and immunotherapeutic advances in pediatric brain tumors.

Brain tumors are the leading cause of childhood cancer-related deaths. Similar to adult brain tumors, pediatric brain tumors are classified based on histopathological evaluations. However, pediatric brain tumors are often histologically inconsistent with adult brain tumors. Recent research findings from molecular genetic analyses have revealed molecular and genetic changes in pediatric tumors that are necessary for appropriate classification to avoid misdiagnosis, the development of treatment modalities, and the clinical management of tumors. As many of the molecular-based therapies developed from clinical trials on adults are not always effective against pediatric brain tumors, recent advances have improved our understanding of the molecular profiles of pediatric brain tumors and have led to novel epigenetic and immunotherapeutic treatment approaches currently being evaluated in clinical trials. In this review, we focus on primary malignant brain tumors in children and genetic, epigenetic, and molecular characteristics that differentiate them from brain tumors in adults. The comparison of pediatric and adult brain tumors highlights the need for treatments designed specifically for pediatric brain tumors. We also discuss the advancements in novel molecularly targeted drugs and how they are being integrated with standard therapy to improve the classification and outcomes of pediatric brain tumors in the future.

Methylation Profiling of Medulloblastoma in a Clinical Setting Permits Sub-classification and Reveals New Outcome Predictions.

Medulloblastoma (MB) is the most common childhood malignant brain tumor and is a leading cause of cancer-related death in children. DNA methylation profiling has rapidly advanced our understanding of MB pathogenesis at the molecular level, but assessments in Saudi Arabian (SA)-MB cases are sparse. MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless (WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3), and Group 4 (G4) tumors. The WNT-MB and SHH-MB subgroups are characterized by gain-of function mutations that activate oncogenic cell signaling, whilst G3/G4 tumors show recurrent chromosomal alterations. Given that each subgroup has distinct clinical outcomes, the ability to subgroup SA-FPPE samples holds significant prognostic and therapeutic value. Here, we performed the first assessment of MB-DNA methylation patterns in an SA cohort using archival biopsy material (FPPE n = 49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3, and G4). Furthermore, methylation analysis was able to reclassify tumors that could not be sub-grouped through next-generation sequencing, highlighting its superior accuracy for MB molecular classifications. Independent assessments demonstrated known clinical relationships of the subgroups, exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes, with a high prevalence in females, high metastatic rates, and a large number of tumor-associated deaths. Taking our results together, we demonstrate that DNA methylation profiling enables the robust sub-classification of four disease sub-groups in archival FFPE biopsy material from SA-MB patients. Moreover, we show that the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning the identification of aggressive G4 tumors. These findings have important implications for future clinical disease management in MB cases across the Arab world.

Clinical management and genomic profiling of pediatric low-grade gliomas in Saudi Arabia.

Pediatric Low Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes. The treatment modality dictates the outcome and optimizing patient management can be challenging. In this study, we profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. We detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1-3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). Interestingly, we identified a GOPC-ROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low grade glioma. The patient underwent gross total resection (GTR). The patient is currently disease free. To our knowledge this is the first report of GOPC-ROS1 fusion in PLGG. Taken together, we reveal the genetic characteristics of pLGG patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG.

Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency.

Primary brain tumors are a leading cause of cancer-related morbidity and mortality in children. Glioblastoma (GBM) is a high-grade astrocytoma that occurs in both children and adults and is associated with a poor prognosis. Despite extensive study in recent years, the clinical management of these tumors has remained largely unchanged, consisting of surgical resection, conventional chemotherapy, and radiotherapy. Although the etiology and genomic drivers in GBM are diverse, constitutional mismatch repair-deficiency (CMMRD) syndrome is a rare, recessively inherited disease with a predisposition to gliomagenesis. CMMRD results from biallelic mutations in one of the mismatch repair genes including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and post-meiotic segregation increased 2 (PMS2). In this report, we present the case of a 5-year-old female with GBM and CMMRD due to an MSH6 homozygous c.1883G>A mutation, who continues to experience an exceptional and durable response (9 months) to the immune checkpoint inhibitor (ICPI) nivolumab. Our patient presented with acute neurologic decline and increased intracranial pressure. Neuroimaging studies revealed a large left frontoparietal mass requiring neurosurgical decompression and resection. Histopathologic analyses resulted in a diagnosis of de novo GBM that was BRAF wild type and negative for programmed death-ligand 1 protein expression. She received standard-of-care treatment with surgery, radiation therapy, and temozolomide; however, the tumor recurred 3 months after the initial diagnosis. Molecular analyses of tumor and blood tissues revealed an MSH6 homozygous c.1883G>A mutation consistent with CMMRD. Given her CMMRD status, she was treated with nivolumab (3 mg/kg doses every 2 weeks for 36 weeks) and showed a 60% reduction in tumor size, improved clinical symptoms, and an ongoing durable response lasting 10 months to date. Our study highlights a durable response to the ICPI nivolumab in a pediatric patient with recurrent/refractory CMMRD-associated GBM. We show that incorporating genomic and/or molecular testing for CMMRD into routine pediatric oncology clinical care can identify a subset of patients likely to benefit from ICPI. KEY POINTS: Constitutional mismatch repair-deficiency (CMMRD) syndrome, alternatively known as biallelic mismatch repair deficiency syndrome, occurs in subset of pediatric cancer patients, including those with primary brain tumors.Patients from Arab and other developing countries are predicted to have higher incidence of CMMRD due to high prevalence of consanguinity.Integration of molecular and/or genomic testing into routine clinical care for pediatric cancer patients is important to identify patients with CMMRD syndrome.Patient with CMMRD-associated cancers may show increased responsiveness to immune checkpoint inhibitors.To the authors' knowledge, this is the first report in the Arab world of a durable response to immune checkpoint inhibitors in a pediatric glioblastoma patient.

A case of molecularly profiled extraneural medulloblastoma metastases in a child.

BACKGROUND: Extraneural metastases are relatively rare manifestations of medulloblastoma. CASE PRESENTATION: We present the case of a young boy with group three MYCN-amplified medulloblastoma. He received multimodal chemotherapy consisting of gross total resection followed by postoperative craniospinal radiation and adjuvant chemotherapy. The patient developed extraneural metastases 4 months after the end of therapy. Literature review identifies the poor prognosis of MYCN-amplified medulloblastomas as well as extraneural metastases; we review the current limitations and future directions of medulloblastoma treatment options. CONCLUSION: To the best of our knowledge, this is the first molecularly characterized report of extraneural metastases of medulloblastoma in a child.