Cancer and Noonan Syndrome

Noonan Syndrome (NS) is a chromosomal genetic disorder and as such can cause many varied and wide ranging pathologies. One of the most worrying health implications of a NS diagnosis is an increased chance of developing cancer; particularly in childhood. There are several blood-based cancers that occur in NS at a higher rate than the general population. These cancers include Juvenile Myelomonocytic Leukemia (JMML), Acute Myelogenous Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL). Solid tumours such as rhabdomyosarcoma, granular cell tumour, Sertoli cell tumour, Neuroblastoma, Dysembryoplastic Neuroepothelial Tumors (DNT) and glial cell tumours are also noted in the medical literature.

How common is Cancer in Individuals with Noonan Syndrome?
The increased risk of all childhood cancers in NS is 8.1 times higher than the general population. Thankfully, this risk drops to 3.5 times by adulthood.  In regards to cancer incidence within NS the population, cancer can occur in as many as 10% of children with NS.

Why is cancer more prevalent in Noonan Syndrome?
NS is one of many diseases considered a ‘RASopathy’. The RAS pathway is a process whereby cell surface receptors are transduced (or ‘turned on’) and messages are sent that either activate or de-activate certain functions within the cell. Thus, the RAS pathway is critical to cell proliferation, survival, differentiation and metabolism. Because of these roles mutations in the RAS pathway can lead to oncogenesis – the creation of abhorrent cell divisions or mutations which cause cancer. This unfortunately means that people who possess any of the RASopathies carry an inherently increased risk of cancer. The increased risk of cancer for all RASopathies is 10.5 times higher than the general population.

The RAS pathway mutations that cause dysregulated signalling within the cell are also responsible for other systemic issues associated with NS; namely pulmonary stenosis, hypertrophic cardiomyopathy, thrombocytopenia and lymphedema. RAS signalling errors have also been implicated in autoimmune conditions, inflammation and are responsible for reduced growth and delayed development.

As research progresses it is becoming evident which mutations are implicated in specific conditions. For example upregulation of RAS signalling in PTNP11, NRAS, KRAS, NF1 and CBL mutations are implicated in the development of JMML. A study solely looking at individuals with NS from PTNP11 mutations identified a 5.6% risk of cancer.

For more information on RASopathies we recommend this video: https://noonansyndrome.com.au/what-are-the-rasopathies/

Recommendations and Future Research
This information about increased cancer risk can understandably be extremely worrying for people with NS and their caregivers.  Whilst knowledge and awareness of these cancer risks can be stressful and anxiety inducing it is also beneficial in that it allows proactive steps to be taken.

Some researchers recommend that all NS children be systematically evaluated for clinical signs of malignancy (splenomegaly, hepatomegaly, blood tests) at least every 3 months for the first year of life and twice during the second year of life.  Other researchers believe immunological surveillance is not warranted as the overall risk is low compared to the invasiveness of regular assessments.

Ultimately the decision to begin surveillance is one solely for people with NS and their families. Regular assessments that yield negative results may reduce stress and anxiety levels; the importance of which can’t be overstated. It is also important to note that the forms of cancer associated with NS all have highly successful treatment rates particularly when detected early.

If you or your family have any questions or concerns about cancer and NS please feel free to contact the NSAA here: https://noonansyndrome.com.au/contact/

There are academic research papers on this topic available to download on our NSAA website: https://noonansyndrome.com.au/research/

References
Flex, E.et.al.(2014). Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Human Molecular Genetics Vol. 23, No. 16 4315–4327.

Jongmans, M.C.J.et.al. (2011). Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. European Journal of Human Genetics, Vol.19, 870–874.

Mohamed Bentires-Alj, A.(2004). Activating Mutations of the Noonan Syndrome-Associated SHP2/PTNP11 Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia. Cancer Research, Vol. 64, 8816-8820.

Siegfried, A. et.al.(2016). Noonan Syndrome, PTNP11 Mutations, and Brain Tumors. A Clinical Report and Review of the Literature. American Journal of Medical Genetics. Vol. 173, 1061-1065.

Strullu, M.et.al(2014). Juvenile Myelomonocytic Leukaemia and Noonan Syndrome. Journal of Medical Genetics, Vol. 51, 689-697.