Contribution of germline PALB2 variants to an unselected and prospectively registered pancreatic cancer patient cohort in Pakistan

Importance: Gastrointestinal (GI) cancers are the second leading cause of cancer-related deaths worldwide. Observations: The global challenges GI cancers pose are high, especially in middle- and low-income countries. Patients with these cancers present with symptoms of poor appetite, weight loss, heartburn, abdominal pain, fatigue, and anaemia. Several risk factors contribute to GI cancers, including age, gender, obesity, pathogenic infections, smoking cigarettes, alcohol consumption, and dietary habits. Most of these cancers are sporadic. However, some patients are at high risk because of a family history of GI cancers. Systemic diseases affect multiple organs, and their chronic occurrence elicits inflammatory responses at various sites. These diseases also contribute to GI cancers. Conclusion and Relevance: In this review, we discuss that untreated systemic diseases, including diabetes, hepatitis, AIDS, ulcers, and hypertension, can potentially lead to GI cancers if they remain untreated for a longer period. Systemic diseases initiate oxidative stress, inflammatory pathways, and genetic manipulations, which altogether confer risks to GI cancers. Here, we describe the association between systemic diseases and their underlying mechanisms leading to GI cancers.

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“…Germline mutations in GI cancer susceptibility genes, including MLH1, MSH2, MSH6, APC, CDKN2A, CDH1 and PALB2 are reported. [ 36 - 38 ]…”

Section: Major Risk Factors Of Gi Cancersmentioning

confidence: 99%

“…Germline mutations in GI cancer susceptibility genes, including MLH1, MSH2, MSH6, APC, CDKN2A, CDH1 and PALB2 are reported. [36][37][38] Other GI diseases Several diseases of the GI tract, if untreated, may develop into cancer. Gastritis, a stomach inflammation, if chronically persists, can cause gastric cancer.…”

Section: Hereditary Factorsmentioning

confidence: 99%

Systemic Diseases and Risk of Developing Gastrointestinal Cancer.

Malkani

Rashid

2023

J Cancer Allied Spec

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Prevalence of BRCA1 and BRCA2 germline variants in an unselected pancreatic cancer patient cohort in Pakistan

Muhammad,

Azeem,

Arif

et al. 2023

Hered Cancer Clin Pract

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Background BRCA1 and BRCA2 (BRCA1/2) are the most frequently investigated genes among Caucasian pancreatic cancer patients, whereas limited reports are available among Asians. We aimed to investigate the prevalence of BRCA1/2 germline variants in Pakistani pancreatic cancer patients. Methods One hundred and fifty unselected and prospectively enrolled pancreatic cancer patients were comprehensively screened for BRCA1/2 germline variants using denaturing high-performance liquid chromatography and high-resolution melting analyses, followed by DNA sequencing of the variant fragments. The novel variants were analyzed for their pathogenic effect using in-silico tools. Potentially functional variants were further screened in 200 cancer-free controls. Results Protein truncating variant was detected in BRCA2 only, with a prevalence of 0.7% (1/150). A frameshift BRCA2 variant (p.Asp946Ilefs*14) was identified in a 71-year-old male patient of Pathan ethnicity, with a family history of abdominal cancer. Additionally, we found a novel variant in BRCA2 (p.Glu2650Gln), two previously reported variants in BRCA1 (p.Thr293Ser) and BRCA2 (p.Ile2296Leu) and a recurrent nonsense variant in BRCA2 (p.Lys3326Ter). These variants were classified as variants of uncertain significance (VUS). It is noteworthy that none of these VUS carriers had a family history of pancreatic or other cancers. Conclusions In this first study, BRCA1/2 pathogenic variant is identified with a low frequency in pancreatic cancer patients from Pakistan. Comprehensive multigene panel testing is recommended in the Pakistani pancreatic cancer patients to enhance genetic understanding in this population.

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Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review

Pantaleo,

Forte,

Fasano

et al. 2023

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. While population-wide screening recommendations for PDAC in asymptomatic individuals are not achievable due to its relatively low incidence, pancreatic cancer surveillance programs are recommended for patients with germline causative variants in PDAC susceptibility genes or a strong family history. In this study, we sought to determine the prevalence and significance of germline alterations in major genes (ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, TP53) involved in PDAC susceptibility. We performed a systematic review of PubMed publications reporting germline variants identified in these genes in PDAC patients. Overall, the retrieved articles included 1493 PDAC patients. A high proportion of these patients (n = 1225/1493, 82%) were found to harbor alterations in genes (ATM, BRCA1, BRCA2, PALB2) involved in the homologous recombination repair (HRR) pathway. Specifically, the remaining PDAC patients were reported to carry alterations in genes playing a role in other cancer pathways (CDKN2A, STK11, TP53; n = 181/1493, 12.1%) or in the mismatch repair (MMR) pathway (MLH1, MSH2, MSH6, PMS2; n = 87/1493, 5.8%). Our findings highlight the importance of germline genetic characterization in PDAC patients for better personalized targeted therapies, clinical management, and surveillance.

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Contribution of germline PALB2 variants to an unselected and prospectively registered pancreatic cancer patient cohort in Pakistan

Cited by 3 publications

References 53 publications

Systemic Diseases and Risk of Developing Gastrointestinal Cancer.

Systemic Diseases and Risk of Developing Gastrointestinal Cancer.

Prevalence of BRCA1 and BRCA2 germline variants in an unselected pancreatic cancer patient cohort in Pakistan

Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review

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