Poster Presentation ESA-SRB 2023 in conjunction with ENSA

The Genetic Landscape of Familial Non-Medullary Thyroid Cancer (FANTOM): Protocol for a multi-centre cohort study (#240)

Jessica Bindra 1 2 3 , Roderick Clifton-Bligh 1 2 3 , Matti Gild 1 2 3
  1. Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
  2. The Kolling Institute, St Leonards, NSW, Australia
  3. Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

Background: Familial non-medullary thyroid cancer (FNMTC) can be either syndromic or, more commonly, non-syndromic. In syndromic disease a driver germline mutation is known, such as Cowden syndrome, familial adenomatous polyposis and DICER1 syndrome, while in non-syndromic disease there is limited understanding of its genetic basis. There is an unmet need to investigate the genetic landscape of non-syndromic FNMTC as it carries poorer prognosis when compared to its syndromic and sporadic counterparts.1-5 Identifying contributing genetic factors may pave the way to create appropriate screening guidelines and eventually identify targeted therapies to improve outcomes.

Objectives: (1) To describe the multi-centre experience of patients with syndromic FNMTC, in turn alerting clinicians to facilitate timely recognition, surveillance, management and genetic counselling and testing of family members where required; and (2) To identify novel genetic contributors in patients with non-syndromic FNMTC through whole genome sequencing (WGS).

Design and Methods: Royal North Shore Hospital (RNSH) will coordinate a two-part multi-centre study, involving retrospective collection of clinicopathologic data and prospective collection of blood samples for WGS. Recruitment will commence at RNSH. We will include adults > 18 years with FNMTC (i.e. differentiated thyroid cancer, DTC) based on the presence of at least TWO first-degree relatives with DTC. The control group will include unaffected family members > 40 years with benign-appearing thyroid ultrasound and/or fine needle aspirate biopsy. Outcome measures will include pathogenic and likely pathogenic mutations in FNMTC identified by WGS and the association between genetic mutation(s) identified and clinical phenotype of non-syndromic FNMTC.

Analysis Plan:  We will perform WGS on FNMTC cases and familial unaffected controls. If syndromic loci negative, we will examine for shared variants within each nuclear family case. Analysis will include shared variants across all FNMTC cases and exclude these identified shared variants in controls (via GnomAD, 1000g, sporadic DTC cases from TCGA).

  1. Mazeh H, Benavidez J, Poehls JL, et al. In patients with thyroid cancer of follicular cell origin, a family history of nonmedullary thyroid cancer in one first-degree relative is associated with more aggressive disease. Thyroid 2012;22(1):3-8.
  2. Lee YM, Yoon JH, Yi O, et al. Familial history of non-medullary thyroid cancer is an independent prognostic factor for tumor recurrence in younger patients with conventional papillary thyroid carcinoma. J Surg Oncol 2014;109(2):168-73.
  3. Tavarelli M, Russo M, Terranova R, et al. Familial Non-Medullary Thyroid Cancer Represents an Independent Risk Factor for Increased Cancer Aggressiveness: A Retrospective Analysis of 74 Families. Front Endocrinol (Lausanne). 2015 Aug 3;6:117.
  4. Park YJ, Ahn HY, Choi HS, et al. The long-term outcomes of the second generation of familial nonmedullary thyroid carcinoma are more aggressive than sporadic cases. Thyroid 2012;22(4):356-62.
  5. Capezzone M, Sagnella A, Cantara S, et al. Risk of Second Malignant Neoplasm in Familial Non-Medullary Thyroid Cancer Patients. Front Endocrinol (Lausanne). 2022 Mar 4;13:845954.