Functional consequences of germline mutations in a novel non-RET medullary thyroid cancer susceptibility gene

PURPOSE To compare the risk of neoplastic progression by germline mutation status versus family history without a known germline mutation (familial risk) among individuals with an increased risk for pancreatic cancer who are undergoing surveillance. METHODS Of 464 high-risk individuals in the Cancer of the Pancreas Screening program at Johns Hopkins Hospital who were undergoing pancreatic surveillance, 119 had a known deleterious germline mutation in a pancreatic cancer susceptibility gene; 345 met family history criteria for pancreatic surveillance but were not known to harbor a germline mutation. We used next-generation sequencing to identify previously unrecognized germline mutations among these 345 individuals. We compared the development of pancreatic cancer, high-grade dysplasia, or clinically worrisome features, adjusting for competing mortality, among all germline mutation carriers with the risk of progression in a cohort without a known germline mutation. RESULTS Fifteen (4.3%) of 345 individuals classified as having familial risk had a previously unrecognized pancreatic cancer susceptibility gene mutation (nine that involved ATM, two BRCA2, one BRCA1, one PALB2, one TP53, and one CPA1). The cumulative incidence of pancreatic cancer, high-grade dysplasia, or worrisome features on pancreatic imaging was significantly higher in the germline mutation risk group (n = 134) than in the familial risk group (n = 330 [for pancreatic cancer, hazard ratio, 2.85; 95% CI, 1.0 to 8.18; P = .05]). CONCLUSION The cumulative incidence of pancreatic cancer is significantly higher among individuals with an identifiable deleterious germline mutation in a pancreatic cancer susceptibility gene than it is among individuals with a strong family history but no identified mutation. Gene testing of individuals who meet criteria for pancreatic surveillance on the basis of their family history may better define those most at risk for neoplastic progression.

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Article Commentary: Medullary Thyroid Cancer: An Update for Surgeons

The American Surgeon ◽

10.1177/000313481508100102 ◽

2015 ◽

Vol 81 (1) ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Faris K. Azar ◽

Stephanie L. Lee ◽

Jennifer E. Rosen

Keyword(s):

Thyroid Cancer ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Progressive Disease ◽

Medullary Thyroid Cancer ◽

Germline Mutations ◽

Current Management ◽

Future Directions ◽

Medullary Thyroid ◽

Individualized Management

Medullary thyroid carcinoma is uncommon but accounts for approximately 4 to 5 per cent of all thyroid cancers. Although most cases are sporadic, close to one-fourth of cases result from germline mutations in the RET proto-oncogene. These mutations are clinically important because they predict the earliest age of medullary thyroid cancer diagnosis and clinical aggressiveness, which guide individualized management. This review covers the presentation, diagnosis, workup, current management, and future directions of the management of medullary thyroid carcinoma. Today's chance for cure depends on early and appropriate surgical resection. Further investigation of the cellular signaling pathways shown to be essential for the growth and spread of medullary thyroid carcinoma remains an active field with hope for providing targeted systemic therapy for patients with progressive disease.

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Identification of SPRY4 as a novel candidate susceptibility gene for familial non-medullary thyroid cancer

Thyroid ◽

10.1089/thy.2020.0290 ◽

2021 ◽

Author(s):

Inês J. Marques ◽

Inês Gomes ◽

Marta Pojo ◽

Carolina Pires ◽

Margarida M. Moura ◽

...

Keyword(s):

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Susceptibility Gene ◽

Medullary Thyroid

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Clinical actionability of universal sequencing for germline cancer susceptibility gene mutations among patients with colorectal cancer: A prospective study.

Journal of Global Oncology ◽

10.1200/jgo.2019.5.suppl.63 ◽

2019 ◽

Vol 5 (suppl) ◽

pp. 63-63

Author(s):

Wu Jiang ◽

Peirong Ding

Keyword(s):

Colorectal Cancer ◽

Hereditary Cancer ◽

Cancer Susceptibility ◽

Susceptibility Gene ◽

Germline Mutations ◽

Hereditary Cancer Syndromes ◽

Tailored Treatment ◽

History Of ◽

Cancer Susceptibility Gene ◽

Cancer Syndromes

63 Background: Genetic predisposition is an important cause of colorectal cancer (CRC). Previous studies have demonstrated that universal sequencing in unselected CRC patients with multi-gene panel could detect more hereditary cancer syndromes. However, it is unclear whether this strategy would change clinical management for the affected individuals. Methods: We prospectively enrolled a consecutive cohort of 486 CRC patients, comprising of unselective patients aged no more than 70 years and patients older than 70 years with hereditary risk features. All participants received germline testing using a comprehensive panel of 81 genes associated with various hereditary cancer syndromes. Results: Fifty-two pathogenic or likely pathogenic mutations were discovered in 51 (10.5%, 51/486) patients, including 20 (4.1%) Lynch syndrome, 11 (4.1%) germline mutations with known CRC risk, and 20 (4.1%) in other cancer susceptibility genes not traditionally associated with CRC. Among them, 21 (4.3%) mutation-positive patients would have been left undiagnosed if they only adhered to present guidelines. Nearly seventy percent (36/51) of the mutation-positive patients were found to carry clinicalactionable germline mutations, for whom enhanced screening and/or tailored treatment was recommended.CRC location, multiple CRC diagnoses, personal history of malignancy, or family history of malignancy was not significantly related to the presence of a mutation in non-CRC susceptibility genes. Conclusions: Universal germline sequencing for cancer susceptibility gene among CRC patients substantially identified more individuals with hereditary cancer syndrome and actionable germline mutations, and these patients might benefit from enhanced surveillance and better tailored treatment. Clinical trial information: NCT03365986.

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