RET-positive cancer is a type of cancer caused by a mutation or abnormal re-arrangement of the RET gene, which codes for a cell membrane receptor and member of the tyrosine protein kinase family of proteins. This leads to abnormal activation of the cell membrane receptor, basically resulting in the “on-off” switch to get stuck in the “on” position and causing these abnormal cells to multiply and spread - thereby “driving” the cancer growth.

Testing the cancer by sending a tissue sample from a tumor, or by sending a blood sample for a circulating ‘cell free DNA’ (cf DNA) blood test to a laboratory, to check for specific genetic changes is the only way to detect cancer drivers like RET. If the test result is positive for a RET mutation or abnormal rearrangement of the RET gene, this information can help to identify treatment and clinical research options.

RET driver mutations occur most commonly in Lung cancer and in several types of inherited and sporadic thyroid cancers, but RET gene mutations can also be seen in small numbers of patients with paraganglioma, ovarian and breast, pancreatic, bladder and colorectal cancers, among others.(1,2)

  • Abnormal re-arrangement or abnormal fusion of the RET gene occurs in 1-2% of all lung adenocarcinomas (also called Non-small cell lung cancer, or NSCLC). Although this is a small percentage of overall lung cancer cases, given that lung cancer is the number one cause of cancer related deaths and that around 1.8 million new lung cancer cases are reported annually worldwide, the number of new RET positive lung cancer patients diagnosed each year is still considerable - about 20,000-30,000 people yearly.


    Overall, NSCLC is more common among women, and RET fusions associated with NSCLC are more prevalent in younger patients who have never or rarely smoked.(3) The most frequent abnormal RET fusion partner genes in NSCLC are RET-KIF5B followed by RET-CCDC6, though at least 30 fusion partner genes have been identified to date(4). The significance of these fusion variants in terms of overall prognosis remains unclear.

  • ©LUNGevity Foundation. Used with permission.

  • Those more likely to have RET positive lung cancer are:

    • Younger
    • Never Smokers
    • Women more commonly than men

    NSCLC or lung adenocarcinoma is more common in women overall, and RET fusions associated with NSCLC are more prevalent in younger patients who have never or rarely smoked. Abnormal fusion of the RET gene occurs in 1-2% of all lung adenocarcinomas, which is about 30,000 people annually.

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References

1. Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23(8):1988-1997. doi:10.1158/1078-0432.CCR-16-1679

2. Li AY, McCusker MG, Russo A, et al. RET fusions in solid tumors. Cancer Treat Rev. 2019;81:101911. doi:10.1016/j.ctrv.2019.101911

3. Subbiah V, Yang D, Velcheti V, Drilon A, Meric-Bernstam F. State-of-the-art strategies for targeting RET-dependent cancers. J Clin Oncol. 2020;38(11):1209-1221. doi:10.1200/JCO.19.02551

4. Mulligan LM. GDNF and the RET receptor in cancer: new insights and therapeutic potential. Front Physiol. 2019;9:1873. doi:10.3389/fphys.2018.01873

RET positive Thyroid Cancer

Papillary thyroid carcinoma is the most frequent thyroid cancer overall and can be seen with exposure to ionizing radiation. (1) RET rearrangements have been reported in approximately 20% of papillary thyroid cancers, with abnormal fusions between RET and CCDC6 or NCOA4 genes seen most commonly. (2) Although medullary thyroid carcinoma represents 5-10% of all thyroid cancers, activating RET gene abnormalities occur in over 90% of hereditary and approximately 40%-60% of sporadic medullary thyroid carcinoma cases. (3) In contrast to the RET fusion alterations found in Papillary thyroid carcinoma, the RET abnormalities found in Medullary Thyroid Carcinoma are primarily activating point mutations.

The typical age of presentation of sporadic Medullary Thyroid Cancer is in the fifth or sixth decade, and slightly more common in women. In contrast, familial and inherited cases of Medullary Thyroid Cancer usually present in those younger than age 20.(4) The identification of RET mutations is relevant to the early diagnosis of hereditary Medullary Thyroid Cancer, and the prognosis of sporadic Medullary Thyroid Cancer.

The role of the RET re-arrangements in Papillary Thyroid Cancer is less relevant but still important in patient management, particularly for deciding if or when a targeted therapy should be initiated. (5)

More information about Thyroid Cancers of all types and a comprehensive list of resources can be found at ThyCa.org.

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References

1. Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011; 7: 569–580

2. Gautschi Oliver, Rich TA, Reckamp KL et al. Analysis of Cell-Free DNA from 32,989 Advanced Cancers Reveals Novel Co-occuring Activating RET Alterations and Oncogenic Signaling Pathway Aberrations. Clinical Cancer Research Clin Cancer Res October 1 2019 (25) (19) 5832-5842

3. Chu Ying-Hsia, Lloyd Ricardo V. Medullary Thyroid Carcinoma: Recent Advances Including MicroRNA Expression. Endocr Pathol. 2016 Dec;27(4):312-324)

4. Sippel Rebecca S, Chen Herbert, Roy Madhuchhanda. Current Understanding and Management of Medullary Thyroid Cancer. Sept 2013;18(10):1093-1100

5. Romei Cristina, Ciampi Raffaele, Elisei Rossella. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol. 2016 Apr;12(4):192-202.