McCune Albright syndrome is a genetic predisposition to intraductal papillary and mucinous neoplasms of the pancreas associated pancreatic cancer in relation with GNAS somatic mutation – a case report

Supplemental Digital Content is available in the text


Introduction
McCune-Albright syndrome (MCAS) is a rare disorder characterized by polycystic fibrous dysplasia, precocious puberty, and café au lait spots. It is caused by somatic, post-zygotic, with mosaic distribution, GNAS activating mutations. [1] In addition to other hepatobiliary neoplasms, [2,3] IPMN have been associated with MCAS.
Somatic activating mutations of the G-protein alpha stimulatory subunit (Gsa subunit) encoded by the GNAS gene (GNAS) have been reported in up to 70% of pancreatic intraductal papillary mucinous neoplasms (IPMN), [4][5][6][7] that is a precursor of pancreatic adenocarcinoma. In this setting, GNAS mutations, known to lead to elevated intracellular cAMP levels and activation of downstream dependent pathways, [1] open new clinical insights on IPMN. As an example, IPMN intestinal pattern of differentiation is associated with GNAS mutation [8] underlining the functional consequences of GNAS activating mutation. Once symptomatic, pancreatic adenocarcinoma is associated with a dismal prognosis. Identifying individuals at risk and detecting early lesions are crucial to improve patient's outcome. Several conditions have been found to be associated with an increased risk of pancreatic adenocarcinoma, and targeted screening of high-risk individuals is important.
The aim of the present study is to examine the mutation status of GNAS in a patient with McCune Albright Syndrome and IPMN who underwent pancreatic resection.

Case report
A 50-year old woman, 144 cm for 58 kg, initially presented with abdominal pain. Patient has provided informed consent for publication of the case. She was previously diagnosed with McCune Albright Syndrome (MCAS) with severe fibrous dysplasia and precocious puberty. She had a past medical history of total thyroidectomy, and multiple surgery for fractures. Cross sectional imaging (Fig. 1) and endoscopic ultrasonography reveled a global main pancreatic duct dilatation over 10 mm associated with a cephalic 25-mm enhanced mural nodule with portal vein lateral abutment, without distant metastasis. Fineneedle aspiration pathology confirmed an IPMN related colloid pancreatic adenocarcinoma. Leucocyte and duodenum juice deoxyribose nucleic acid (DNA) analysis [9] (endoscopically collected from secretin-stimulated pancreatic juice; Supplemental Video, http://links.lww.com/MD/D482) revealed the same Gprotein alpha stimulatory sub-unit (Gsa subunit) gene (GNAS) (NM_000516) activating mutation c.601C>T (p.Arg201Cys) (Fig. 2). The same mutation was also detected in plasma circulating DNA. The patient underwent pancreaticoduodenectomy after 3 months of FOLFIRINOX neoadjuvant chemotherapy. Pathological examination revealed an invasive pancreatic colloid adenocarcinoma (Supplemental Fig., http://links.lww. com/MD/D483) (ypT2 N1 R0) arising from intestinal subtype IPMN (ie, MUC1-, MUC2+, MUC5AC+ immunohistochemistry) with a major (over 90%) response to chemotherapy. Genetic analysis of the IPMN revealed a GNAS (NM_000516) activating mutation c.601C>T (p.Arg201Cys), which was not detected at a 2% variant allele frequency threshold in the adjacent normal pancreas. No KRAS or other driver mutation was detected in the IPMN associated cancer with a targeted 50 genes NGS panel. Imaging and medical work-up, plasma circulating tumor DNA, Formalin-Fixed Paraffin Embedded and pancreatic juice somatic mutation analysis technics are available in Supplemental Material, http://links.lww.com/MD/D484. Thirty months after surgery, the patient is alive with recurrence (bone only metastasis).

Discussion
Intraductal papillary mucinous neoplasm (IPMN) can be seen as a "recent" disease and has only been clearly individualized in the mid 80's. Since then, its diagnosis, description, comprehension and management have been significantly improved. [10][11][12][13] The adenoma-carcinoma sequence leading to the development of pancreatic adenocarcinoma is currently under investigation but include as major events telomere shortening, KRAS activating mutation, loss and/or mutation of SMAD4 and p53. [14] Since recent whole-exome analysis, GNAS mutations also appear to have a key role in IPMN pathogenesis. [15] With KRAS, it is therefore, one of the 2 most prevalent mutations in these tumors. It may occur alone or in association with KRAS activating mutations and could define a specific progression pathways in IPMN-associated carcinoma. [15][16][17] GNAS-activating mutations are reported in both IPMN and MCAS, and IPMN is a MCAS associated lesion. [18,19] This emphasizes the important role of GNAS in pancreatic tumorigenesis. [5] GNASdriven pancreatic tumorigenesis is associated with IPMN intestinal phenotype [8] and colloid pancreatic adenocarcinoma, [16] and a less aggressive disease, with better long-term outcome. [20] IPMN occur most of the time as a sporadic disease. Some [21][22][23] previously reported familial forms of IPMN in few kindred, suggesting predisposing genetic alteration. So far they were not found, and neither BRCA2, p16 nor CDKN2A were constitutionally mutated or lost. [21] If familial forms of pancreatic adenocarcinoma are now well known, [24,25] familial forms of pancreatic adenocarcinoma have not been formally described.
First, this observation underlines the need for a specific screening for high-risk patients identified by their known genetic predisposition, and MCAS should be considered as a pancreatic cancer predisposition syndrome. Second, it is now possible to determine preoperatively GNAS status from plasma circulating DNA, duodenum juice DNA collected after secreting stimulation test, or DNA from extracted paraffin-embedded tissue from EUS-FNA and to identify at least intestinal IPMN phenotype. If up to now this information has a limited value, [26] it is likely that in a near future it will help to tailor pancreatic cyst and IPMN management. [27] Overall, this observation provides additional evidence of MCAS as a new genetic predisposition to IPMN associated pancreatic cancer, and consequently the need for a specific screening in this population.