What is Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC)?
Hereditary Leiomyomatosis and Renal Cell Cancer, or HLRCC, is a rare disease that causes smooth muscle tumors and aggressive kidney cancer. These smooth muscle tumors have a high chance of reoccurrence in the skin. HLRCC develops through the deficiency of Fumarate hydratase (FH), which is needed to stimulate the creation of malate [1]. Malate plays an important role in ATP production, which is used as an energy source inside cells [2]. All of this alters various cellular signaling pathways, causing irregular cell regulation leading to tumors.
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More about the FH gene:
The FH gene is responsible for the conversion of Fumarate to Malate in the Krebs cycle. This means that FH genes are used in the mitochondria of the cell. FH encodes an protein known as fumarate hydratase, which is formed through the transcription of the FH gene (which is used as a template) and translation of said protein [1]. This protein acts as an enzyme by lowering the amount of energy needed for the two change these Fumarate to Malate [3]. Due to the lower energy, water is able to attach to one of the carbons of Fumarate, causing the double bond between the carbons to break, leading to the formation of Malate [4].
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As previously mentioned, when there is a mutation or lack of the FH gene, some cellular signaling pathways are altered. These cellular signaling pathways are [1]:
- Increased H1F1A Activity
- Increased NRF2 Activity
- Weakened iron homeostasis
What are the symptoms of HLRCC?
Since Hereditary Leiomyomatosis and Renal Cell Cancer develop due to insufficient amounts of Fumarate hydratase, a variety of symptoms can occur. The first signs of HLRCC are small, firm bumps or lumps that grow on the skin that are not cancerous. Another symptom is pressure or pain in the pelvic area, along with heavy menstrual periods, which is caused by uterine fibroids (noncancerous growths in the uterus). There is an increased risk of aggressive kidney cancer that has the ability to spread throughout the body and cause more cancer growth [8].
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Prevalence and Inheritance level of HLRCC
Hereditary Leiomyomatosis and Renal Cell Cancer is a rare autosomal dominant condition that could appear in up to 20% of families. Since this condition is caused by a rare dominant gene, an exact prevalence rate is difficult to determine. Most people with this condition are diagnosed between 18 and 52 years of age [9].
The FH gene is located on chromosome 1 (autosomal chromosome). HLRCC occurs when one copy of a chromosome has a mutated copy of the FH gene and another copy of a chromosome with the regular FH gene. Since this is an autosomal dominant allele, only one copy needs to be present in the genome to cause this condition [10]. This also makes this allele difficult to track in a pedigree [1]. |
References:
[1] Ooi, A. (2020, April). Advances in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) research. Seminars in cancer biology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078051/
[2] Gough, L. A., Sparks, S. A., McNaughton, L. R., Higgins, M. F., Newbury, J. W., Trexler, E., Faghy, M. A., & Bridge, C. A. (2021, December). A critical review of Citrulline Malate Supplementation and Exercise Performance. European journal of applied physiology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571142/#:~:text=The%20primary%20role%20of%20malate,2002).
[3] Lewis, T. (2023, April 24). Biochemistry, proteins enzymes. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK554481/#:~:text=Enzymes%20generally%20do%20not%20add,to%20require%20less%20activation%20energy.
[4] PL;, C.-T. D. (2009, November 24). The tricarboxylic acid cycle in human skeletal muscle: Is there a role for nutritional intervention?. Current opinion in clinical nutrition and metabolic care. https://pubmed.ncbi.nlm.nih.gov/10678684/
5] Cimmino, F., Avitabile, M., Lasorsa, V. A., Montella, A., Pezone, L., Cantalupo, S., Visconte, F., Corrias, M. V., Iolascon, A., & Capasso, M. (2019, February 26). HIF-1 transcription activity: HIF1A driven response in Normoxia and in hypoxia - BMC medical genetics. BioMed Central. https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-019-0767-1
[6] Wu, S., Lu, H., & Bai, Y. (2019, May). Nrf2 in cancers: A double-edged sword. Cancer medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536957/#:~:text=The%20constitutive%20activation%20of%20Nrf2,capacity%20of%20cancer%20stem%20cells.
[7] Wang, Y., Yu, L., Ding, J., & Chen, Y. (2018, December 27). Iron Metabolism in Cancer. International journal of molecular sciences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337236/
[8] NORD. (2023, November 20). Hereditary leiomyomatosis and renal cell carcinoma - symptoms, causes, treatment: Nord. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/hereditary-leiomyomatosis-and-renal-cell-carcinoma/
[9] Menko, F. H., Maher, E. R., Schmidt, L. S., Middelton, L. A., Aittomäki, K., Tomlinson, I., Richard, S., & Linehan, W. M. (2014, December). Hereditary leiomyomatosis and renal cell cancer (HLRCC): Renal cancer risk, surveillance and treatment. Familial cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574691/
[10] HLRCC Foundation. (2023, February 19). Hereditary leiomyomatosis and renal cell cancer (HLRCC) - overview of genetic kidney cancer syndrome. YouTube. https://www.youtube.com/watch?v=rX1BWQvjqN4
[2] Gough, L. A., Sparks, S. A., McNaughton, L. R., Higgins, M. F., Newbury, J. W., Trexler, E., Faghy, M. A., & Bridge, C. A. (2021, December). A critical review of Citrulline Malate Supplementation and Exercise Performance. European journal of applied physiology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571142/#:~:text=The%20primary%20role%20of%20malate,2002).
[3] Lewis, T. (2023, April 24). Biochemistry, proteins enzymes. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK554481/#:~:text=Enzymes%20generally%20do%20not%20add,to%20require%20less%20activation%20energy.
[4] PL;, C.-T. D. (2009, November 24). The tricarboxylic acid cycle in human skeletal muscle: Is there a role for nutritional intervention?. Current opinion in clinical nutrition and metabolic care. https://pubmed.ncbi.nlm.nih.gov/10678684/
5] Cimmino, F., Avitabile, M., Lasorsa, V. A., Montella, A., Pezone, L., Cantalupo, S., Visconte, F., Corrias, M. V., Iolascon, A., & Capasso, M. (2019, February 26). HIF-1 transcription activity: HIF1A driven response in Normoxia and in hypoxia - BMC medical genetics. BioMed Central. https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-019-0767-1
[6] Wu, S., Lu, H., & Bai, Y. (2019, May). Nrf2 in cancers: A double-edged sword. Cancer medicine. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536957/#:~:text=The%20constitutive%20activation%20of%20Nrf2,capacity%20of%20cancer%20stem%20cells.
[7] Wang, Y., Yu, L., Ding, J., & Chen, Y. (2018, December 27). Iron Metabolism in Cancer. International journal of molecular sciences. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337236/
[8] NORD. (2023, November 20). Hereditary leiomyomatosis and renal cell carcinoma - symptoms, causes, treatment: Nord. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/hereditary-leiomyomatosis-and-renal-cell-carcinoma/
[9] Menko, F. H., Maher, E. R., Schmidt, L. S., Middelton, L. A., Aittomäki, K., Tomlinson, I., Richard, S., & Linehan, W. M. (2014, December). Hereditary leiomyomatosis and renal cell cancer (HLRCC): Renal cancer risk, surveillance and treatment. Familial cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574691/
[10] HLRCC Foundation. (2023, February 19). Hereditary leiomyomatosis and renal cell cancer (HLRCC) - overview of genetic kidney cancer syndrome. YouTube. https://www.youtube.com/watch?v=rX1BWQvjqN4