Abstract
Background
Pancreatic adenocarcinoma is one of the most aggressive malignancies with extremely low survival rate. Studies have shown that the exploration of key genes can provide a basis for targeted treatment of these patients. The genomic architecture of the Pakistani pancreatic adenocarcinoma patients remains unexplored. Keeping the scenario in place, the current study aims to analyse 88 cancer related genes in Pakistani pancreatic adenocarcinoma patients in order to elucidate candidate gene(s) for targeted molecular therapy.
Methods and results
A total 18 patients were included in the study initially and FFPE tumor samples were obtained. After confirmation of diagnosis and appropriate tumor content, DNA was extracted. Based on the quality and quantity of the extracted DNA, six pancreatic adenocarcinoma tumor samples were selected. Following to this, all the samples were subjected to targeted sequencing (Axen Cancer Panel 1). Variant detection was done and clinical significance of identified variants was assessed using ClinVar database. Targeted sequencing of tumor samples revealed a total of 29 alterations in the coding region of various genes. Among these five pathogenic variants were found in KRAS, BRCA1, TP53 and APC genes.
Conclusion
This is the first study that explores genes involved in pancreatic adenocarcinoma from the Pakistani population. Results obtained from the pilot study can guide us about the key genetic players in the Pakistani pancreatic adenocarcinoma population. This can lead to our better understanding of the molecular targeted therapies for these patients and designing future researches on larger sample size.
Similar content being viewed by others
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 71:209–249
Kuehn BM (2020) Looking to long-term survivors for improved pancreatic cancer treatment. JAMA 324:2242–2244
Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL et al (2018) Folfirinox or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 379:2395–2406
Berlin JD, Feng Y, Catalano P, Abbruzzese JL, Philip PA, McWilliams RR et al (2018) An intergroup randomized phase II study of bevacizumab or Ccetuximab in combination with gemcitabine and in combination with chemoradiation in patients with resected pancreatic carcinoma: a trial of the ECOG-ACRIN cancer research group (E2204). Oncology 94:39–46
Ioka T, Okusaka T, Ohkawa S, Boku N, Sawaki A, Fujii Y et al (2015) Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized phase III trial. Jpn J Clin Oncol 45:439–448
Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C et al (2013) Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer 49:2633–2642
Mie T, Sasaki T, Takeda T, Okamoto T, Mori C, Furukawa T et al (2021) Treatment outcomes of erlotinib plus gemcitabine as late-line chemotherapy in unresectable pancreatic cancer. Jpn J Clin Oncol 51:1416
Waters AM, Der CJ (2018) KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med 8:a031435
Connor AA, Denroche RE, Jang GH, Lemire M, Zhang A, Chan-Seng-Yue M et al (2019) Integration of genomic and transcriptional features in pancreatic cancer reveals increased cell cycle progression in metastases. Cancer Cell 35:267–282
Shen GQ, Aleassa EM, Walsh RM, Morris-Stiff G (2019) Next-generation sequencing in pancreatic cancer. Pancreas 48:739–748
Amundadottir LT (2016) Pancreatic cancer genetics. Int J Biol Sci 12:314
Guo S, Shi X, Shen J, Gao S, Wang H, Shen S et al (2020) Preoperative detection of KRAS G12D mutation in ctDNA is a powerful predictor for early recurrence of resectable PDAC patients. Br J Cancer 122:857–867
Lee Y, Lee S, Sung JS, Chung HJ, Lim AR, Kim JW (2021) Clinical application of targeted deep sequencing in metastatic colorectal cancer patients: actionable genomic alteration in K-MASTER project. Cancer Res Treat 53:123
Han MR, Lee SH, Park JY, Hong H, Ho JY, Hur SY et al (2020) Clinical implications of circulating tumor DNA from ascites and serial plasma in ovarian cancer. Cancer Res Treat 52:779
Lee Y, Jeon JH, Goh SH, Roh H, Yun JY, Kwon NJ et al (2019) The clinical impact of family history of cancer in female never-smoker lung adenocarcinoma. Lung Cancer 136:15–22
Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S et al (2018) ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 46:D1062–D1067
Landrum MJ, Chitipiralla S, Brown GR, Chen C, Gu B, Hart J et al (2020) ClinVar: improvements to accessing data. Nucleic Acids Res 48:D835–D844
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P et al (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518:495–501
Winkler EC, Wiemann S (2016) Findings made in gene panel to whole genome sequencing: data, knowledge, ethics–and consequences? Expert Rev Mol Diagn 16:1259–1270
Yachida S, White CM, Naito Y, Zhong Y, Brosnan JA, Macgregor-Das AM (2012) Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin Cancer Res 18:6339–6347
Schlitter AM, Segler A, Steiger K, Michalski CW, Jäger C, Konukiewitz B (2017) Molecular, morphological and survival analysis of 177 resected pancreatic ductal adenocarcinomas (PDACs): identification of prognostic subtypes. Sci Rep 7:1–2
Nishiwada S, Sho M, Cui Y, Yamamura K, Akahori T, Nakagawa K (2021) A gene expression signature for predicting response to neoadjuvant chemoradiotherapy in pancreatic ductal adenocarcinoma. Int J Cancer 148:769–779
Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC (2016) Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531:47–52
Rosen MN, Goodwin RA, Vickers MM (2021) BRCA mutated pancreatic cancer: a change is coming. World J Gastroenterol 27:1943
Liede A, Malik IA, Aziz Z, De los Rios P, Kwan E, Narod SA (2002) Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan. Am J Hum Genet 71:595–606
Rashid MU, Zaidi A, Torres D, Sultan F, Benner A, Naqvi B (2006) Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients. Int J Cancer 119:2832–2839
Rashid MU, Muhammad N, Bajwa S, Faisal S, Tahseen M, Bermejo JL (2016) High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. BMC Cancer 16:673
Rashid MU, Muhammad N, Naeemi H, Khan FA, Hassan M, Faisal S (2019) Spectrum and prevalence of BRCA1/2 germline mutations in Pakistani breast cancer patients: results from a large comprehensive study. Hered Cancer Clin Pract 17:1–13
Fernandes GC, Michelli RA, Galvão HC, Paula AE, Pereira R, Andrade CE et al (2016) Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at risk for hereditary breast cancer and characterization of its genetic ancestry. Oncotarget 7:80465
Lee JS, Oh S, Park SK, Lee MH, Lee JW, Kim SW et al (2018) Reclassification of BRCA1 and BRCA2 variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort. J Med Genet 55:794–802
Zanella I, Merola F, Biasiotto G, Archetti S, Spinelli E, Di Lorenzo D (2017) Evaluation of the ion torrent PGM sequencing workflow for the routine rapid detection of BRCA1 and BRCA2 germline mutations. Exp Mol Pathol 102:314–320
Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L et al (2019) Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: an ENIGMA resource to support clinical variant classification. Hum Mutat 40:1557–1578
Zuntini R, Ferrari S, Bonora E, Buscherini F, Bertonazzi B, Grippa M et al (2018) Dealing with BRCA1/2 unclassified variants in a cancer genetics clinic: does cosegregation analysis help? Front Genet 9:378
Pesaran T, Karam R, Huether R, Li S, Farber-Katz S, Chamberlin A et al (2016) Beyond DNA: an integrated and functional approach for classifying germline variants in breast cancer genes. Int J Breast Cancer 2016:2469523
Borun P, Kubaszewski L, Banasiewicz T, Walkowiak J, Skrzypczak-Zielinska M, Kaczmarek-Rys M et al (2014) Comparative-high resolution melting: a novel method of simultaneous screening for small mutations and copy number variations. Hum Genet 133:535–545
De Lellis L, Aceto GM, Curia MC, Catalano T, Mammarella S, Veschi S et al (2013) Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms. PLoS ONE 8:e81194
Obul J, Itoga S, Abliz M, Sato K, Ishige T, Utsuno E et al (2012) High-resolution melting analyses for gene scanning of APC, MLH1, MSH2, and MSH6 associated with hereditary colorectal cancer. Genet Test Mol Biomarkers 16:406–411
Juanes M (2020) Cytoskeletal control and wnt signaling—APC’s dual contributions in stem cell division and colorectal cancer. Cancers 12:3811
Bournet B, Muscari F, Buscail C, Assenat E, Barthet M, Hammel P (2016) KRAS G12D mutation subtype is a prognostic factor for advanced pancreatic adenocarcinoma. Clin Transl Gastroenterol 7:e157
Han CW, Jeong MS, Jang SB (2021) Understand KRAS and the quest for anti-cancer drugs. Cells 10:842
Al-Qasem AJ, Toulimat M, Eldali AM, Tulbah A, Al-Yousef N, Al-Daihan SK et al (2011) TP53 genetic alterations in Arab breast cancer patients: novel mutations, pattern and distribution. Oncol Lett 2:363–369
Gillet E, Alentorn A, Doukouré B, Mundwiller E, van Thuij H, Reijneveld JC et al (2014) TP53 and p53 statuses and their clinical impact in diffuse low grade gliomas. J Neurooncol 118:131–139
Neyaz A, Husain N, Gupta S, Kumari S, Arora A, Awasthi NP et al (2018) Investigation of targetable predictive and prognostic markers in gallbladder carcinoma. J Gastrointest Oncol 9:111
Dutta S, Pregartner G, Rücker FG, Heitzer E, Zebisch A, Bullinger L et al (2020) Functional classification of TP53 mutations in acute myeloid leukemia. Cancers 12:637
Liu Q, Tong D, Liu G, Yi Y, Xu J, Yang X et al (2018) A novel BRCA2 mutation in prostate cancer sensitive to combined radiotherapy and androgen deprivation therapy. Cancer Biol Ther 19:669–675
Liu Y, Zhang Y, Hua W, Li Z, Wu B, Liu W (2019) Clinical and molecular characteristics of thalamic gliomas: retrospective report of 26 cases. World Neurosurg 126:e1169-1182
Zhou Y, Guo D, Zhang Y (2020) Association of microRNA-21 with p53 at mutant sites R175H and R248Q, clinicopathological features, and prognosis of NSCLC. Mol Ther Oncolytics 19:208–217
Alsner J, Yilmaz M, Guldberg P, Hansen LL, Overgaard J (2000) Heterogeneity in the clinical phenotype of TP53 mutations in breast cancer patients. Clin Cancer Res 6:3923–3931
Donehower LA, Soussi T, Korkut A, Liu Y, Schultz A, Cardenas M et al (2019) Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas. Cell Rep 28:1370–1384
Food and Drugs Administration USA (2021) http://www.fda.gov. Accessed 12 Oct 2021
Tamai T, Kaneko M, Narukawa M (2021) Comparison of efficacy outcomes of anticancer drugs between Japanese patients and the overall population. Int Journal Clin Oncol 26:296–304
Funding
The study was funded by University Research Council, Aga Khan University Hospital (183027SUR).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Authors declare that they have no conflict of interest.
Ethical approval
The study was approved by the Institutional Ethical Review Committee of Aga Khan University Hospital (2020-2101-8768).
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Ali, S.M., Adnan, Y., Ahmad, Z. et al. Genetic landscape of pancreatic adenocarcinoma patients: a pilot study from Pakistan. Mol Biol Rep 49, 1341–1350 (2022). https://doi.org/10.1007/s11033-021-06964-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-021-06964-z