The email caught Alice (alias) in panic.

She has witnessed so many cancer cases, along with other severe health troubles, in her family. Something is not right in the family, she thought, and she needed to find it out. She started by inquiring the health conditions of her family members. The results were astonishing: the cancer affected not just her cousins, but also her parents, uncles and aunties, and her grandpas, grandmas, great uncles and great aunties.

She documented all these medical conditions in the family and tried to consult a doctor. However, what specialty of the doctor should she seek for? She did not know. She thought all these conditions must be from the genes of the family. Therefore, she went on to get a genetic test. The results came back in an email seemingly to confirm her suspicion: she carries a V804 mutation in the gene of RET, which was defined as “pathogenic” in the report. However, it did not answer any of her questions. Instead, more anxiety arose in her mind: how much risk does that mean to her? Would she get cancer sooner or later? Would her children also get the "bad gene"? The risk for her children would be her top concern. If unfortunately that becomes true, how should she explain it to her children? Would they be haunted mentally for a lifetime? 

Alice had a million questions, and needed to find the answers. She went on the internet to crunch all the information. It seems that RET mutations affect thyroid more often. Therefore, she reached out to doctors of endocrinology in several big hospitals, email by email, sometimes by phone calls. Most of the time she was totally ignored. Once in a while she got a reply from the doctors, but she/he simply turned her away by saying that she/he was not specialized in such a problem. 

Feeling desperate, Alice talked to a friend who works in NIH; actually, our lab manager Andie (alias). Andie told me about Alice's frustration, and asked me to help. The first thing that made me wonder was those doctors' responses. I know quite a few clinicians who are regarded as the top experts in their fields nationwide or even worldwide. As expected, they all are extremely busy, and some of them are terrible at replying to emails. However, if the message was about a patient, I usually received their response in the same day, or even in 5 minutes. That's the good and required quality of a clinician. I did not understand how those doctors' turned Alice away.

Nevertheless, the first thing I needed to figure out was the consequence of this RET mutation, and then I would know who I should ask. Without previous knowledge, finding the symptoms associated with genetic changes is like finding a needle in a haystack (or searching for a needle dropped into the water of an ocean, in Chinese style). There are so many possibilities. Were all the conditions in Alice's family really attributed to this mutation (so-called “germline” mutation), or it happens only to her (“somatic mutation”)? Should I consider only the shared features of those cancer types? The majority of Alice's family, both father's and mother's sides, originated from East Europe Jews. Could the diseases occur because of other rare genetic variation?  

After the first virtual meet up, Alice and I had some more follow up conversation. She did not stop her own efforts, kept asking more doctors and detailing the medical conditions in her family. As I went deep in her family medical record, I called her to ask for more details. She could not control the feeling of frustration and uncertainty: “I got no response from the doctors whom I asked. Please help me.” She said it with a weeping and trembling voice. I told her, we will pursue- both the gene and the doctor- together. 

Although I narrowed down the range of possible diseases linked to RET mutations, they were still too vague to discuss with an expert, especially I could not be sure if this is a germline mutation or a somatic mutation). I felt stuck. 

After two days, Alice emailed me, “I am pretty sure what in my family is MEN2A (endocrine adenomatosis type 2A) syndromes”. I checked the description of the syndromes; it matched the health condition of her family members very well. Most importantly, MEN2A is caused by a few types of RET mutations, and patients frequently develop medullary thyroid carcinoma early in life. However, the RET mutation Alice carries causes a milder form of MEN2A, so that is the reason that she is cancer-free for now. I emailed back: “I am very convinced it’s MEN2A in your family, and now I believe I can find whom to ask.” 

One of the research focuses of the Pediatric Oncology Branch in NCI is hereditary cancer syndromes, and I remember that investigators there have published studies in medullary thyroid carcinoma, so I checked the papers. Bingo! I wrote an email to the lead investigator, and the physician scientist kindly agreed immediately to discuss with Alice. Later she told me the physician answered many of her questions, and referred her to an endocrinologist for further evaluation for future risk and prophylactic surgery. Even more, if the doctor decides prophylactic surgery is necessary, she is eligible to a clinical study for MEN2A in the Surgical Branch of NCI.

Alice wrote to thank me. I told her that, without her persistent search for the information, I could not find the answer and the doctor to help so promptly. She is a layman in science, but her great pursuit for the answers was inspiring and admirable for any scientist. She taught me much more than I could help her.     

Update: Alice has convinced more of her family members going to take the genetic tests, and all the results confirmed that the RET mutation is inherited through at least four generations in her family. Currently she and her endocrinologist is evaluating when the prophylactic surgery to remove thyroid glands should be performed.