Hereditary genetics…..where to focus

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 and I cannot guarantee this post will contain all of them.
Apparently, 5-10% of 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.

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 many people already know about genetic issues via family connections. But there are tumour dispositions that might be similar to known genetic presentations with NETs. For example, I guess if you have 2 tumors found in (say) parathyroid and pancreas, it should at least raise a suspicion for the MEN1 syndrome 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.  This is in fact one of the suggested 10 questions I list in my questions article (see more here). However, as I hinted above, there are known connections which increase suspicions, and many people will have already been told of their risk from parents and siblings.  But before you all run off and get tested, you need to understand two things, firstly you need professional testing and not the sort of thing you find cheap online.  Secondly there are known linkages about genetic issues with NETs so always talk to your doctors first to avoid nugatory effort and expense.  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:

When should genetic testing be performed in patients with neuroendocrine tumours?

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

Pituitary tumours

Pituitary tumours have traditionally been treated as a separate group; however, there is mounting interest in reclassifying them as Neuroendocrine Tumours (PitNET). There is increasing evidence in the literature for a genetic predisposition for some subtypes of pituitary tumour, but discussion of this is beyond the scope of the review above. However, 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.