Unexpected Pathogenic RET p.V804M Variant Leads to the Clinical Diagnosis and Management of Medullary Thyroid Carcinoma

Breen, Katelyn M.; Dwan, Meaghan; Barletta, Justine A.; Vatnick, Donna Rachel; Stokes, Samantha; Block, Caroline; Doherty, Gerard M.; Cohn, Aviva; Marqusee, Ellen; Garber, Judy E.; Rana, Huma Q.

doi:10.12659/ajcr.927415

Cited by 5 publications

(2 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For patients found to have genetic risk of melanoma, endocrine neoplasms, and/or renal cell carcinoma, there are efficacious guidelines for screening that should be utilized [30][31][32][33][34][35][36]. We have previously reported on the frequency of unexpected germline PVs among patients with BC [37,38] and on intercepted genetic cancers [39]. Information on BC hormone receptor subtype was only available for some patients and therefore was not analyzed.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception

Bychkovsky

Yussuf

et al. 2023

Breast Cancer Res Treat

Self Cite

View full text Add to dashboard Cite

Purpose Herein, we report the frequency and distribution of germline pathogenic variants (PVs) among females with breast cancer (BC) and at least one other non-BC who underwent multi-gene panel testing (MGPT). Among females with PVs diagnosed first with BC or ovarian cancer (OC), we sought to enumerate the frequency of subsequent PV-associated cancers. Methods Females with BC and cancer of ≥ 1 other site (multiple primary cancers, MPC) who underwent MGPT through Ambry Genetics from March 2012 to December 2016 were included if they had testing of at least 21 genes of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53). Phenotypic data were abstracted from test requisition forms and clinical notes. Results Of 6,617 evaluable patients, most were White (70.8%) and median age at first cancer, second cancer, and MGPT was 49 (interquartile range [IQR]: 18), 59 (IQR: 16), and 63 (IQR: 16) years, respectively. PVs were found among 14.1% (932/6617) of the overall cohort and in 16.4% (440/2687) of females who were diagnosed first with BC. Among those, 55.2% (243/440) had an actionable PV associated with a subsequent cancer diagnosis including 150 OCs. Of the 2443 females with breast and ovarian cancer, few (n = 97, 9.5%) were diagnosed first with OC, limiting our analysis. Conclusions Females with MPC, including BC, have a high frequency of germline PVs (14.1%). These data delineate the opportunities for intercepting subsequent cancers associated with genetic risk among females diagnosed first with BC.

show abstract

Section: Discussionmentioning

confidence: 99%

Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception

Bychkovsky

Yussuf

et al. 2023

Breast Cancer Res Treat

Self Cite

View full text Add to dashboard Cite

show abstract

“…Genetic factors are also essential in this integrated germline somatic evaluation approach. Recent large-scale sequencing obtained from cohorts free from ascertainment bias demonstrated some cancer genes or alleles might not be as highly penetrant as once considered or may exhibit variable expressivity (22,23,(52)(53)(54). These observations suggest the presence of genetic modifiers affecting the presentation of disease, which makes a strong argument in favor of assessing germline variants in parallel with patient's tumor profile.…”

Section: Discussionmentioning

confidence: 99%

An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes

et al. 2022

Self Cite

View full text Add to dashboard Cite

Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in PMS2, MSH6, SDHC, SHDA, and TP53 were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.

show abstract

Familial Medullary Thyroid Cancer: Five-year Review of the Most Frequent Mutations in the RET Gene: An Update

Castañeda¹,

Vences²,

Gordillo³

et al. 2022

SJMS

View full text Add to dashboard Cite

Background: Familial Medullary Thyroid Cancer (FMTC) is hereditary in 25% of cases. Patients with an inherited form of FMTC usually have a germline mutation in the RET proto-oncogene (10q11.2); these mutations generally occur in exons 10 (codons 618 and 620) and 11 (codons 630, 631, and 634). Methods: A narrative review of articles focused on the pathology of familial medullary thyroid cancer was carried out using the next databases PubMed, ScienceDirect, BMC, Springer, Frontiers, PMC, Wiley Online Library, Cold Spring Harbor and ELSEVIER. This search was carried out between August and September 2021. Results: 19 studies were selected in which the following mutations were found: five studies (26.31%) reported mutation in exon 10; three studies (15.78%) in exon 11; three studies in exon 13 (one of them associated with a rare mutation in exon 7) (10.52% plus 5.26%); three studies (15.78%) in exon 14; two studies (10.52%) in exon 15; two (10.52%) in exon 16; and one (5.26%) rare FMTC NO RET. The two most frequent mutations were in codons 620 of exon 10 and 804 of exon 14. Conclusion: The findings of this review are consistent with the medical literature, finding the most common RET mutations in exon 10 and codon 620. It is essential that in patients with a presumptive diagnosis, genetic studies (identification of germline mutations in the RET proto-oncogene, located on chromosome 10q11.2) be performed.

show abstract

Unexpected Pathogenic RET p.V804M Variant Leads to the Clinical Diagnosis and Management of Medullary Thyroid Carcinoma

Cited by 5 publications

References 34 publications

Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception

Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception

An integrated somatic and germline approach to aid interpretation of germline variants of uncertain significance in cancer susceptibility genes

Familial Medullary Thyroid Cancer: Five-year Review of the Most Frequent Mutations in the RET Gene: An Update

Contact Info

Product

Resources

About