Dataset Information

Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.

ABSTRACT:

Context

Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease.

Objective

To investigate for novel genes causing parathyroid cancer.

Methods

We analyzed the germline DNA of 17 patients with "sporadic" PC and 3 with atypical parathyroid tumors (APTs) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants.

Results

We identified germline FLCN variants in 3 unrelated patients with PC. The 2 frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome, while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing; however, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant.

Conclusion

The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy.

SUBMITTER: Jha S

PROVIDER: S-EPMC10505536 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.

Jha Smita S Welch James J Tora Rana R Lack Justin J Warner Andrew A Del Rivero Jaydira J Sadowski Samira M SM Nilubol Naris N Schmidt Laura S LS Linehan W Marston WM Weinstein Lee S LS Simonds William F WF Agarwal Sunita K SK

The Journal of clinical endocrinology and metabolism 20230901 10

<h4>Context</h4>Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease.<h4>Objective</h4>To investigate for novel genes causing parathyroid cancer.<h4>Methods</h4>We analyzed the germline DNA of 17 patients with "sporadic" PC and 3 with atypical parathyroid tumors (APTs) who did not ...[more]

PMID: 36935552

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Project description:In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency.SignificanceEmerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.

Dataset Information

Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.

Context

Objective

Methods

Results

Conclusion

Publications

Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.

Similar Datasets

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