Skip to main content

Identification of mutant K-RAS in pituitary macroadenoma



RAS genes are among the most frequently mutated genes in cancer, where their mutation frequency varies according to the distinct RAS isoforms and tumour types. Despite occurring more prevalent in malignant tumours, RAS mutations were also observed in few benign tumours. Pituitary adenomas are examples of benign tumours which vary in size and aggressiveness. The present study was performed to investigate, via liquid biopsy and tissue analysis, the presence of K-RAS mutations in a pituitary macroadenoma.


Molecular analysis was performed to investigate K-RAS mutations using the droplet digital PCR (ddPCR) method by evaluating both plasma (liquid biopsy) and the solid tumour of a patient diagnosed with a giant clinically non-functioning pituitary tumour.


The patient underwent surgical resection due to visual loss, and the histopathological analysis showed a gonadotrophic pituitary macroadenoma. The molecular analysis revealed the presence of mutant K-RAS both in the plasma and in the tumour tissue which, to our knowledge, has not been previously reported in the literature.


Our findings highlight the exceptional capacity of the digital PCR in detecting low frequency mutations (below 1%), since we detected, for the first time, K-RAS mutations in pituitary macroadenoma. The potential impact of K-RAS mutations in these tumours should be further investigated.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. Zenonos K (2013) RAS signaling pathways, mutations and their role in colorectal cancer. World J Gastrointest Oncol.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Li S, Balmain A, Counter CM (2018) A model for RAS mutation patterns in cancers: finding the sweet spot. Nat Rev Cancer 18:767–777

    Article  CAS  Google Scholar 

  3. Hobbs GA, Der CJ, Rossman KL (2016) RAS isoforms and mutations in cancer at a glance. J Cell Sci 129:1287–1292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gil Ferreira C, Aran V, Zalcberg-Renault I et al (2014) KRAS mutations: variable incidences in a Brazilian cohort of 8,234 metastatic colorectal cancer patients. BMC Gastroenterol 14:73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Aran V, Masson Domingues P, Carvalho de Macedo F et al (2018) A cross-sectional study examining the expression of splice variants K-RAS4A and K-RAS4B in advanced non-small-cell lung cancer patients. Lung Cancer 116:7–14.

    Article  PubMed  Google Scholar 

  6. Prior IA, Hood FE, Hartley JL (2020) The frequency of Ras mutations in cancer. Cancer Res 80:2969–2974

    Article  CAS  Google Scholar 

  7. Kato S, Lippman SM, Flaherty KT, Kurzrock R (2016) The conundrum of genetic “Drivers” in benign conditions. J Natl Cancer Inst.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Coura BP, Bernardes VF, de Sousa SF et al (2019) KRAS mutations drive adenomatoid odontogenic tumor and are independent of clinicopathological features. Mod Pathol.

    Article  PubMed  Google Scholar 

  9. Feng Y, Bommer GT, Zhao J et al (2011) Mutant kras promotes hyperplasia and alters differentiation in the colon epithelium but does not expand the presumptive stem cell pool. Gastroenterology.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wittersheim M, Heydt C, Hoffmann F, Büttner R (2017) KRAS mutation in papillary fibroelastoma: a true cardiac neoplasm? J Pathol Clin Res.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Caimari F, Korbonits M (2016) Novel genetic causes of pituitary adenomas. Clin Cancer Res 22(20):5030–5042

    Article  CAS  Google Scholar 

  12. Daly AF, Rixhon M, Adam C et al (2006) High prevalence of pituitary adenomas: A cross-sectional study in the province of Liège Belgium. J Clin Endocrinol Metab 91(12):4769–4775.

    Article  CAS  PubMed  Google Scholar 

  13. Ostrom QT, Cioffi G, Gittleman H et al (2019) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol 21:v1–v100.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Carneiro CC, Mendes BB, Bastos LG (2015) Adenoma hipofisário: correlação clínica, laboratorial e radiológiCA. Rev da Univ Val do Rio Verde 13:256–269.

    Article  Google Scholar 

  15. Potorac I, Petrossians P, Daly AF et al (2015) Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences. Endocr Relat Cancer.

    Article  PubMed  Google Scholar 

  16. Kasuki L, Raverot G (2020) Definition and diagnosis of aggressive pituitary tumors. Rev Endocr Metab Disord 21:203–208

    Article  Google Scholar 

  17. Chin SO (2020) Epidemiology of functioning pituitary adenomas. Endocrinol Metab 35:237–242.

    Article  CAS  Google Scholar 

  18. Tatsi C, Stratakis CA (2019) The genetics of pituitary adenomas. J Clin Med 9:30.

    Article  CAS  PubMed Central  Google Scholar 

  19. Iacovazzo D, Korbonits M (2016) Gigantism: x-linked acrogigantism and GPR101 mutations. Growth Horm IGF Res 30–31:64–69

    Article  Google Scholar 

  20. Pei L, Melmed S, Scheithauer B et al (1994) H-ras mutations in human pituitary carcinoma metastases. J Clin Endocrinol Metab 78:842–846.

    Article  CAS  PubMed  Google Scholar 

  21. Karga HJ, Alexander JM, Hedley-Whyte ET et al (1992) Ras mutations in human pituitary tumors. J Clin Endocrinol Metab 74:914–919.

    Article  CAS  PubMed  Google Scholar 

  22. Waters AM, Der CJ (2018) KRAS: the critical driver and therapeutic target for pancreatic cancer. Cold Spring Harb Perspect Med 8:a031435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Karachaliou N, Mayo-de-las-Casas C, Molina-Vila MA, Rosell R (2015) Real-time liquid biopsies become a reality in cancer treatment. Ann Transl Med 3(3):36

    PubMed  PubMed Central  Google Scholar 

  24. Haber DA, Velculescu VE (2014) Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. Cancer Discov. 4(6):650–661

    Article  CAS  Google Scholar 

  25. Diaz LA, Polyak K (2013) Tracking tumor resistance using ‘liquid biopsies.’ Nat Med.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mattox AK, Bettegowda C, Zhou S et al (2019) Applications of liquid biopsies for cancer. Sci Transl Med.

    Article  PubMed  Google Scholar 

  27. Olmedillas-López S, García-Arranz M, García-Olmo D (2017) Current and emerging applications of droplet digital PCR in oncology. Mol Diagnosis Ther 21(5):493–510

    Article  Google Scholar 

  28. Dong L, Wang S, Fu B, Wang J (2018) Evaluation of droplet digital PCR and next generation sequencing for characterizing DNA reference material for KRAS mutation detection. Sci Reports 8:9650.

    Article  CAS  Google Scholar 

  29. Pender A, Garcia-Murillas I, Rana S et al (2015) Efficient genotyping of KRAS mutant non-small cell lung cancer using a multiplexed droplet digital PCR approach. PLoS ONE 10:e0139074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Denis JA, Patroni A, Guillerm E et al (2016) Droplet digital PCR of circulating tumor cells from colorectal cancer patients can predict KRAS mutations before surgery. Mol Oncol 10:1221–1231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. De Rubis G, Rajeev Krishnan S, Bebawy M (2019) Liquid biopsies in cancer diagnosis, monitoring, and prognosis. Trends Pharmacol Sci 40(3):172–186

    Article  Google Scholar 

  32. Diaz LA, Bardelli A (2014) Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 32(6):579–586

    Article  Google Scholar 

  33. Myers MB, Mckim KL, Meng F, Parsons BL (2015) Low-frequency KRAS mutations are prevalent in lung adenocarcinomas. Per Med 12:83–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tougeron D, Lecomte T, Pagès JC et al (2013) Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer. Ann Oncol 24:1267–1273.

    Article  CAS  PubMed  Google Scholar 

Download references


We thank the funding agencies (CNPq and FAPERJ), the patient and the Associação Mahatma Gandhi for their support.


This study was funded by the Brazilian agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq Universal 427912/2018–0) and Fundação de Amparo à Pesquisa do Rio de Janeiro (FAPERJ 25191).

Author information

Authors and Affiliations



VA and VMN contributed to the study conception and design. Material preparation, data collection and analysis were performed by VA, MH, PJM, LK, RLM, FA, LC, MRG, VMN. The first draft of the manuscript was written by VA and VMN, and all authors contributed to the final draft. MRG and PNF critically revised the manuscript. All authors have read and approved its final draft for publication.

Corresponding author

Correspondence to Veronica Aran.

Ethics declarations

Conflict of Interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Instituto Estadual do Cérebro Paulo Niemeyer (Approval number: CAAE:90680218.6.1001.8110).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Aran, V., Heringer, M., da Mata, P.J. et al. Identification of mutant K-RAS in pituitary macroadenoma. Pituitary 24, 746–753 (2021).

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Pituitary adenoma
  • K-RAS
  • Macroadenoma
  • Digital PCR
  • Liquid biopsy