Genetics and Neuroendocrine Tumors


In my article ‘Ever wonder what caused your NET’, I concluded that currently, the only known scientifically explained causes for NETs were hereditary/genetic in nature.  This is mostly associated with those who have MEN syndromes (yes, they are a syndrome not a type of tumour) and a few other less common types of NET including Pheochomocytoma/Paraganglioma (Pheo/Para) and Medullary Thyroid Carcinoma (MTC) (the familial version of MTC is often referred to as FMTC). However, please note this does not mean that all those diagnosed with pancreatic, parathyroid, pituarity, Pheo/Para and MTC tumours, will have any hereditary or genetic conditions, many will simply be sporadic tumors.

In recent years, it has become increasingly apparent that a number of Neuroendocrine tumours arise as a result of germline genetic mutations and are inherited in an autosomal dominant pattern. The number of genes implicated is increasing.

Apparently, 5-10% of Gastroenteropancreatic NETs (GEP NETs) are estimated to have a hereditary background. Hereditary syndromes associated with these include Multiple Endocrine Neoplasia (MEN), Von Hippel Lindau (VHL), Neurofibromatosis Type 1 (NF1), Tuberous Sclerosis (TS) and others. People who have a genetic condition may present with the tumors (perhaps along with an associated functional hormone syndrome) and so the genetic condition if there is one, may not be known at this point.

genetics locations
Overview of genes with recurrent mutations in NETs and their distribution accordingly to anatomical location. Please note the percentages on the above diagram may differ depending on where you look).  
Citation: European Journal of Endocrinology 174, 6; 10.1530/EJE-15-0972

How will I know if I am affected? 

Some people do worry about this, often because of what they find on the internet including inside patient forums.  I suspect some people already know via family connections and as an example (there are many), I guess if you have 2 tumors found in (say) parathyroid and pancreas, it should at least raise a suspicion for MEN1 and be investigated.

Many people say how do I know, how do I check and this is obviously a delicate subject.  Of course, your first port of call should be your NET specialist if you suspect or know of any connection.

Thus why I was interested in a paper published in Springer Link – titled “When should genetic testing be performed in patients with neuroendocrine tumours.”  When reading, you’ll find it’s actually much more than that! Check it out here:

Crossref DOI link: https://doi.org/10.1007/s11154-017-9430-3

In this review, the authors examined the features which may lead a clinician to suspect that a patient may have an inherited cause of a NET and they outlined which underlying conditions should be suspected. They also discussed what type of screening may be appropriate in a variety of situations. If there is a way to identify which patients are likely to have a germline mutation, this would enable clinicians to counsel patients adequately about their future disease risk, and allows for earlier detection of at-risk patients through family screening. There’s a couple of minor errors in the text but I’ve contacted the authors who also agreed they should have included the pituitary.

The authors focused on presentations of NETs of the gastrointestinal system, chromaffin cell tumours (Pheochromocytoma and Paraganglioma) and Medullary Thyroid Carcinoma. Pituitary tumors (normally associated with MEN1), were not considered in scope for the review.  Interesting thought, the review includes news of a move by endocrinologists to reclassify ‘Pituitary Adenomas’ as Pituitary NETs (PitNETs). Read the abstract here.  This would appear to be in line with a gradual shift from the benign nomenclature associated with certain NETs to the ‘malignant’ potential of these type of tumors.  The abbreviation is also in line with others, e.g. pNET, SiNET, etc.  A useful reminder that we must stop using the term ‘Carcinoid‘ as this is regressing this extremely useful initiative to highlight the malignant potential of all NETs.

There also appears to be some linkage to the study looking at the possibility of familial Small Intestine NETs (SiNETs).  You can read more about a US registered trial here (with apologies for use of the now defunct term ‘Carcinoid‘).

This is a complex subject and the text above is very basic. If you wish to dig further, the quoted reference is a good read.  Just to emphasise, it’s aim is to provide advice about when to recommend genetic testing for NETs, and in doing so provides some useful reference information.  Please also note they are finding new genetic links all the time so there could be some omissions of recently discovered genes but the article remains good enough as a primer on the subject.  It’s broken down into 4 distinct tumor groupings:

1.  Gastroenteropancreatic (GEP NETs)

2.  Bronchial/Thymic NETs

3.  Pheochromocytoma/Paraganglioma  The familial connection with Pheo/Para is complex. Up to 13 genes have been identified including NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2(SDH5), TMEM127, MAXm EPAS1, FH, MDH2.  Read more here (recent update)The NIH also have a useful section – click here.

4.  Medullary Thyroid Carcinoma

You may also find this article from the National Cancer Institute very useful.  It has a wider scope but a different aim. Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version”

I also noted the UKINETS Guidelines for NETs has a section on genetics and includes something called Carney Complex.

Thanks for reading

Ronny

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Ever wonder what caused your NET?

DNA strand and Cancer Cell

OPINION.  When you’re diagnosed, you go through a whole host of emotions. It’s not just the initial shock, the disbelief, the anxiety and morbid worry produced by the words “you have cancer”, it’s other stuff such as anger and denial.  With the latter, the denial normally wears off as you finally accept the predicament.

In hindsight, the anger is interesting because there can be a mixture of thoughts including “why me“, “what could I have done to head this off“; and would you believe I was even angry that my diagnosis was going to affect my performance at work and even my personal credibility.  We all react differently but in general terms our experiences can be categorised into 3 main areas: initial reaction, distress and then adjustment.

Initially, I was frustrated I didn’t know what had caused my cancer, perhaps my thinking was that I could warn others.  Those feelings soon wore off as I discovered that no-one really knows why people succumb to certain cancers.

If you don’t know what caused your NET, you’re not alone.  According to several studies in the past 10 years, around 40% of cancers are preventable indicating that up to 60% might just be plain bad luck. Clearly this figure varies between cancer types with the biggest culprits being Lung and Skin cancer with too much exposure to tobacco and ultraviolet light respectively. However, the reports also pointed out that people can and will still get these cancers without significant exposure to the commonly preventable causes. The latest study is interesting because it raises the issue that some cancers may be totally unavoidable as they are caused by random errors associated with DNA replication.  This study remains controversial because it undermines government prevention strategies. There’s a balanced article from Cancer Research UK which is a useful read (interesting quote … “Even if, as this study suggests, most individual cancer mutations are due to random chance, the researchers admit that the cancers they cause may still be preventable”).

I carried out some research and discovered the only currently known causes of NETs are heredity/genetic in nature and this only affects a small proportion of all NETs.  As for the remainder, will we ever know?  Perhaps one day but in my opinion, not anytime soon.  One interesting find is a study funded by NET Research Foundation which is designed to discover the molecular causes of a Small Intestine NET (SiNET).  In addition, they will investigate potential environmental causes, including epigenomic and infectious causes.

I often think about what actually caused my NET but I no longer worry about what the answer might be.  I’m the first to admit I could have led a healthier life (like many others) but that may not have had any impact or involvement in my cancer diagnosis.  There doesn’t seem to be any point worrying because the clock cannot be turned back …..even if I knew, I would still have metastatic NETs. However, if the cause of my cancer was connected to a heredity condition, clearly this would be important to know. That’s only my own opinion though.

Thanks for reading

Ronny

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Remember ….. in the war on Neuroendocrine Cancer, let’s not forget to win the battle for better quality of life!


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