SDHA secondary findings in germline testing: counseling and surveillance considerations.

This commentary explores the complexities faced by clinicians when encountering a secondary SDHA pathogenic variant (PV) in patients without a personal or family history of SDHA-related tumors. The increasing use of germline multi-gene panel testing has led to a rise in such secondary findings, necessitating a nuanced approach to counseling, surveillance, and decision-making. We aim to discuss the current data surrounding the penetrance of SDHA PVs, the spectrum of screening guidelines, recommendations for educating individuals and families about their secondary findings, and the need for future research to optimize care for these individuals. Practical recommendations for clinicians dealing with patients with secondary SDHA findings include acknowledging the limitations of existing guidelines, fostering shared decision-making, and considering specialist referrals. Overall, the evolving landscape of SDHA penetrance data warrants ongoing reassessment of surveillance approaches.

Telomere-lengthening germline variants predispose to a syndromic papillary thyroid cancer subtype.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy. 10% to 15% of individuals show familial clustering with three or more affected members, but the factors underlying this risk are unknown. In a group of recently studied individuals with POT1 pathogenic variants and ultra-long telomere length, PTC was the second most common solid tumor. We tested whether variants in POT1 and four other telomere-maintenance genes associated with familial cancer underlie PTC susceptibility. Among 470 individuals, we identified pathogenic or likely pathogenic variants in three genes encoding telomere-binding proteins: POT1, TINF2, and ACD. They were found in 4.5% and 1.5% of familial and unselected cases, respectively. Individuals harboring these variants had ultra-long telomere length, and 15 of 18 (83%) developed other cancers, of which melanoma, lymphoma, and sarcoma were most common. Among individuals with PTC and melanoma, 22% carried a deleterious germline variant, suggesting that a long telomere syndrome might be clinically recognizable. Successive generations had longer telomere length than their parents and, at times, developed more cancers at younger ages. Tumor sequencing identified a single oncogenic driver, BRAF p.Val600Glu, in 10 of 10 tumors studied, but no telomere-maintenance mechanism, including at the TERT promoter. These data identify a syndromic subset of PTCs with locus heterogeneity and telomere lengthening as a convergent mechanism. They suggest these germline variants lower the threshold to cancer by obviating the need for an acquired telomere-maintenance mechanism in addition to sustaining the longevity of oncogenic mutations.

Indolent behavior of malignant Bethesda III nodules compared to Bethesda V/VI nodules.

BACKGROUND: The Bethesda System classifies all fine needle aspiration specimens into one of six categories. We speculated that cancers within each Bethesda category would have distinct clinical behavior. METHODS: This is a retrospective analysis of patients from a single academic medical center with a histologic diagnosis of thyroid cancer who had an initial diagnosis of Bethesda III, IV, V, or VI cytology. RESULTS: A total of 556 cases were included, with 87 cases of Bethesda III, 109 cases of IV, 120 cases of V, and 240 cases of VI. Bethesda III showed similarities with V/VI compared to IV with predominance of papillary thyroid cancer. The interval from diagnosis to surgery was longer in Bethesda III compared to Bethesda V/VI (median 78 vs. 41 days, p<0.001) (Figure 1). Yet, patients with Bethesda III had a higher probability of achieving remission (62 vs.46 %, p<0.03), a lower possibility of recurrence (8 vs. 24%, p<0.001) and a shorter interval to achieve remission (median 1218 vs.1682 days p = 0.02) compared to Bethesda V/VI which did not change after adjusting for age, gender, radioactive iodine therapy, mode of surgery and tumor size. More than 70% of Bethesda III that later presented with recurrence had T3/T4 disease or distant metastasis. CONCLUSIONS: Cancers with Bethesda III cytology had a less aggressive clinical phenotype with better prognosis compared to V/VI despite histological similarities. The time to remission was shorter in Bethesda III despite a longer interval between diagnosis and surgery. The initial cytological diagnosis may guide management.

CHEK2 Founder Variants and Thyroid Cancer Risk.

Background: Germline pathogenic variants in CHEK2 are associated with a moderate increase in the lifetime risk for breast cancer. Increased risk for other cancers, including non-medullary thyroid cancer (NMTC), has also been suggested. To date, data implicating CHEK2 variants in NMTC predisposition primarily derive from studies within Poland, driven by a splice site variant (c.444 + 1G>A) that is uncommon in other populations. In contrast, the predominant CHEK2 variants in non-Polish populations are c.1100del and c.470T>C/p.I157T, representing 61.1% and 63.8%, respectively, of all CHEK2 pathogenic variants in two large U.S.-based commercial laboratory datasets. To further delineate the impact of common CHEK2 variants on thyroid cancer, we aimed to investigate the association of three CHEK2 founder variants (c.444 + 1G>A, c.1100del, and c.470T>C/p.Ile157Thr) on NMTC susceptibility in three groups of unselected NMTC patients. Methods: The presence of three CHEK2 founder variants was assessed within three groups: (1) 1544 NMTC patients (and 1593 controls) from previously published genome-wide association study (GWAS) analyses, (2) 789 NMTC patients with germline exome sequencing (Oncology Research Information Exchange Network [ORIEN] Avatar), and (3) 499 NMTC patients with germline sequence data available in The Cancer Genome Atlas (TCGA). A case-control study design was utilized with odds ratios (ORs) calculated by comparison of all three groups with the Ohio State University GWAS control group. Results: The predominant Polish variant (c.444 + 1G>A) was present in only one case. The proportion of patients with c.1100del was 0.92% in the GWAS group, 1.65% in the ORIEN Avatar group, and 0.80% in the TCGA group. The ORs (with 95% confidence intervals [CIs]) for NMTC associated with c.1100del were 1.71 (0.73-4.29), 2.64 (0.95-7.63), and 2.5 (0.63-8.46), respectively. The proportion of patients with c.470T>C/p.I157T was 0.91% in the GWAS group, 0.76% in the ORIEN Avatar group, and 0.80% in the TCGA group, respectively. The ORs (with CIs) for NMTC associated with c.470T>C/p.I157T were 1.75 (0.74-4.39), 1.52 (0.42-4.96), and 2.31 (0.58-7.90), respectively. Conclusions: Our analyses of unselected patients with NMTC suggest that CHEK2 variants c.1100del and c.470T>C/p.I157T have only a modest impact on thyroid cancer risk. These results provide important information for providers regarding the relatively low magnitude of thyroid cancer risk associated with these CHEK2 variants.

Presumed Pathogenic Germ Line and Somatic Variants in African American Thyroid Cancer.

Background: African American (AA) thyroid cancer patients have worse prognoses than European Americans (EA), which has been attributed to both health care disparities and possible genetic differences. We investigated the impact of both germ line and somatic variants on clinical outcome in a cohort of AA nonmedullary thyroid cancer (NMTC) patients who had received therapeutic intervention from cancer centers. Methods: Whole-exome sequencing was performed on DNA from available blood/normal tissues (N = 37) and paired tumor samples (N = 32) collected from 37 and 29 AA NMTC patients, respectively. Variants with Combined Annotation Depletion Dependent (CADD) score of ≥20 and VarSome Clinical classification of likely pathogenic or pathogenic were classified as presumed pathogenic germ line or somatic variants (PPGVs/PPSVs). PPGVs/PPSVs in cancer-related genes and PPGVs in cardiovascular risk genes were further investigated, and PPGVs/PPSVs associated with African (AFR) ancestry were identified. Results: Among 17 PPGVs identified in 16 cancer predisposition or known cancer-related genes, only WRN was previously known to associate with NMTC predisposition. Among PPSVs, BRAFV600E was most the prevalent and detected in 12 of the 29 (41%) tumors. Examining PPGVs/PPSVs among three patients who died from NMTC, one patient who died from papillary thyroid carcinoma/anaplastic thyroid carcinoma (PTC/ATC) led us to speculate that the PPGV ERCC4R799W may have increased the risk of PPSV TP53R273H acquisition. Among PPGVs identified in 18 cardiovascular risk genes, PPGVs in SC5NA, GYG1, CBS, CFTR, and SI are known to have causal and pathogenic implications in cardiovascular disease. Conclusion: In this cohort, most AA-NMTC patients exhibit favorable outcomes after therapeutic intervention given at cancer centers, suggesting that health care disparity is the major contributor for worse prognoses among AA-NMTC patients. Nevertheless, the clinical impact of PPGVs that might facilitate the acquisition of TP53 tumor mutations, and/or PPGVs that predispose individuals to adverse cardiovascular events, which could be exacerbated by therapy-induced cardiotoxicity, needs to be further explored. Integrated analysis of PPGV/PPSV profiles among NMTC patients with different stages of disease may help to identify NMTC patients who require close monitoring or proactive intervention.

PDPR Gene Variants Predisposing to Papillary Thyroid Cancer.

Background: Papillary thyroid cancer (PTC) is the predominant subtype of thyroid cancer (THCA), and it can cluster in families with an autosomal dominant (AD) inheritance pattern. The aim of this study was to identify novel genes and mechanisms underlying PTC susceptibility. Methods: Our previous investigation of 17 AD PTC families led us to conduct a deeper analysis on one family (Family Q) with whole-genome sequencing data from 3 PTC-affected individuals. In addition, 323 sporadic THCA cases from Avatar data and 12 familial adenomatous polyposis (FAP) individuals with secondary THCA were screened for pyruvate dehydrogenase phosphatase regulatory (PDPR) variants. CRISPR-Cas9 was used to create PDPR-deficient THCA (TPC1) and transformed normal thyroid cell lines (N-Thyori3-1) to study the metabolic consequences of PDPR loss. Results: We found truncating PDPR splice donor variants (NM_017990.4:c.361 + 1G>C) in all affected PTC Family Q members, and another PDPR splice donor variant (NM_017990.4:c.443 + 1G>C) in a sporadic PTC case. In addition, an ultra-rare missense variant was found in an FAP-PTC patient. The PDPR-deficient cells presented with elevated phosphorylation of pyruvate dehydrogenase and altered glucose metabolism, implying that PDPR plays an essential part in regulating glucose metabolism in thyroid cells. Conclusions: Our finding of novel truncating germline variants in PDPR in Family Q and additional cohorts suggests a role for PDPR loss in PTC predisposition. Also, somatic and RNA sequencing from the thyroid carcinoma (Firehouse Legacy) data showed that PDPR gene expression is much lower in THCA tumor tissue compared with matching normal tissue. Thus, PDPR appears to have a loss of function effect on THCA tumorigenesis.

Clinical Impact of Pathogenic Variants in DNA Damage Repair Genes beyond BRCA1 and BRCA2 in Breast and Ovarian Cancer Patients.

Consensus guidelines for hereditary breast and ovarian cancer include management recommendations for pathogenic/likely pathogenic (P/LP) variants in ATM, CHEK2, PALB2, and other DNA damage repair (DDR) genes beyond BRCA1 or BRCA2. We report on clinical management decisions across three academic medical centers resulting from P/LP findings in DDR genes in breast/ovarian cancer patients. Among 2184 patients, 156 (7.1%) carried a P/LP variant in a DDR gene. Clinical follow-up information was available for 101/156 (64.7%) patients. Genetic test result-based management recommendations were made for 57.8% (n = 59) of patients and for 64.7% (n = 66) of patients' family members. Most recommendations were made for moderate-to-high risk genes and were consistent with guidelines. Sixty-six percent of patients (n = 39/59) implemented recommendations. This study suggests that P/LP variants in DDR genes beyond BRCA1 and BRCA2 can change clinical management recommendations for patients and their family members, facilitate identification of new at-risk carriers, and impact treatment decisions. Additional efforts are needed to improve the implementation rates of genetic-testing-based management recommendations for patients and their family members.

Genetic evaluation of patients and families with concern for hereditary endocrine tumor syndromes.

Hereditary endocrine tumor syndromes are rare conditions with overlapping features. It is imperative that healthcare providers differentiate between these syndromes for proper patient care. Advances in genetic testing technologies have increased utilization of genetic counseling and testing in this field; however, few endocrine cancer genetics clinics exist. Two years ago, a genetic counselor (GC) specializing in endocrine cancer genetics was added to the multidisciplinary team of the James Neuroendocrine/Thyroid Clinic at The Ohio State University. Here, we report on this experience. In total, 358 patients were seen. The majority were referred by medical oncology (n = 204; 57%) for a personal history of disease (n = 249; 81%). The most common referral indications were pancreatic neuroendocrine tumors (n = 44; 17%), multiple primary tumors (n = 37; 14%), and pheochromocytoma/paraganglioma (n = 35; 14%). Most patients completed genetic testing after genetic counseling (n = 200; 65%). Targeted gene panel testing was the most common testing ordered (n = 98; 32%). Thirty-one patients (15.5%) had ≥ one likely pathogenic variant (LPV) or pathogenic variant (PV) identified. Approximately 37% (n = 11) did not meet genetic testing guidelines for the gene they tested positive for. The most common genes with LPV/PVs were the SDH genes (n = 8) and MEN1 (n = 7). Referral indications with the highest likelihood of LPV/PVs were paraganglioma, medullary thyroid carcinoma, and multiple primary tumors. We believe this data can provide valuable guidance to healthcare providers who see patients with endocrine neoplasia or who are seeking to establish hereditary endocrine cancer clinics.

Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroendocrine and Adrenal Gland Tumors focus on the diagnosis, treatment, and management of patients with neuroendocrine tumors (NETs), adrenal tumors, pheochromocytomas, paragangliomas, and multiple endocrine neoplasia. NETs are generally subclassified by site of origin, stage, and histologic characteristics. Appropriate diagnosis and treatment of NETs often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine and adrenal tumors and are intended to assist with clinical decision-making. This article is focused on the 2021 NCCN Guidelines principles of genetic risk assessment and counseling and recommendations for well-differentiated grade 3 NETs, poorly differentiated neuroendocrine carcinomas, adrenal tumors, pheochromocytomas, and paragangliomas.

Transcriptome analysis discloses dysregulated genes in normal appearing tumor-adjacent thyroid tissues from patients with papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The molecular characteristics of histologically normal appearing tissue adjacent to the tumor (NAT) from PTC patients are not well characterized. The aim of this study was to characterize the global gene expression profile of NAT and compare it with those of normal and tumor thyroid tissues. We performed total RNA sequencing with fresh frozen thyroid tissues from a cohort of three categories of samples including NAT, normal thyroid (N), and PTC tumor (T). Transcriptome analysis shows that NAT presents a unique gene expression profile, which was not associated with sex or the presence of lymphocytic thyroiditis. Among the differentially expressed genes (DEGs) of NAT vs N, 256 coding genes and 5 noncoding genes have been reported as cancer genes involved in cell proliferation, apoptosis, and/or tumorigenesis. Bioinformatics analysis with Ingenuity Pathway Analysis software revealed that "Cancer, Organismal Injury and Abnormalities, Cellular Response to Therapeutics, and Cellular Movement" were major dysregulated pathways in the NAT tissues. This study provides improved insight into the complexity of gene expression changes in the thyroid glands of patients with PTC.

A novel essential splice site variant in SPTB in a large hereditary spherocytosis family.

BACKGROUND: We studied a large family with 22 individuals affected with autosomal dominant hereditary spherocytosis (HS). METHODS: Genome-wide linkage, whole-genome sequencing (WGS), Sanger sequencing, RT-PCR, and ToPO TA cloning analyses were performed. RESULTS: We revealed a heterozygous G>A transition in the 14q23 locus, at position +1 of the intron 8 donor splice site of the spectrin beta, erythrocytic (SPTB) gene. This splice variant (SPTB c.1064+1G>A) was confirmed by Sanger sequencing and showed complete co-segregation with HS in the family. Further RT-PCR reactions and sequencing analysis indicated that the variant leads to the exclusion of exon 8 and subsequent frameshift in exon 9 and a premature stop codon in SPTB. Translation of the altered allele would lead to a truncation with a loss of all spectrin repeat domains in SPTB protein. CONCLUSION: This variant is novel and has not been found in any databases. We propose that this splice variant explains the spherocytosis phenotype observed in this large family.

Characterizing the function of EPB41L4A in the predisposition to papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common histotype of thyroid carcinoma. The heritability of PTC is high compared to other cancers, but its underlying causes are unknown. A recent genome-wide association study revealed the association of a variant at the 5q22 locus, rs73227498, with PTC predisposition. We report that rs17134155, a variant in high linkage disequilibrium with rs73227498, is located in an enhancer region downstream of coding transcripts of EPB41L4A. Rs17134155 showed significant enhancer activity in luciferase assays, and haplotypes containing the protective allele of this variant conferred a significantly lower risk of PTC. While the index SNP, rs73227498, acted as a significant cis-eQTL for expression of EPB41L4A, rs17134155 was a significant cis-sQTL for the alternative splicing of a non-coding transcript of EPB41L4A, called EPB41L4A-203. We also performed knockdown of EPB41L4A followed by microarray analysis. Some of the top differentially-expressed genes were represented among regulators of the WNT/ß-catenin signaling pathway. Our results indicate that an enhancer region at 5q22 regulates the expression and splicing of EPB41L4A transcripts. We also provide evidence that EPB41L4A expression is involved in regulating growth and differentiation pathways, suggesting that decreased expression of EPB41L4A is a mechanism in the predisposition to PTC.

Assessing thyroid cancer risk using polygenic risk scores.

Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points (P ≤ 1.0 × 10-9). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: Challenges and opportunities in genetic counseling for hereditary endocrine neoplasia syndromes.

The Genetic Counseling Working Group from the 16th International Workshop on Multiple Endocrine Neoplasia (MEN 2019) convened to discuss contemporary challenges and opportunities in the area of genetic counseling for individuals and families affected by hereditary endocrine neoplasia syndromes. As healthcare professionals with multidisciplinary training in human genetics, risk assessment, patient education, psychosocial counseling, and research methodology, genetic counselors bring a unique perspective to working toward addressing these challenges and identifying their subsequent opportunities. This Working Group focused on the following broad areas: (1) genetic counseling resources for endocrine neoplasias, (2) candidate gene discovery, (3) implications of increasingly sensitive and expansive genetic testing technologies for both the germline and the tumors, and (4) situating clinical diagnoses for hereditary endocrine neoplasia syndromes in the context of present-day knowledge.

Variants in LRRC34 reveal distinct mechanisms for predisposition to papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC) demonstrates high heritability and a low somatic mutation burden relative to other cancers. Therefore, the genetic risk predisposing to PTC is likely due to a combination of low penetrance variants. A recent genome-wide association study revealed the association of PTC with a missense variant, rs6793295, at 3q26 in a gene called Leucine Repeat Rich Containing 34 (LRRC34). METHODS: We report the mechanisms of PTC risk at 3q26 using a combination of overexpression, mass spectroscopy, knockdown, transcriptome profiling, migration assays and genetic analysis. RESULTS: We observed differential binding of wild-type and missense LRRC34 to RANBP1. Overexpression of missense LRRC34 reduced RanGTP levels and increased apoptosis. We also identified a second linkage disequilibrium (LD) block upstream of LRRC34 containing regulatory variants with allele-specific expression. Transcriptome profiling of LRRC34 knockdown cells showed changes in genes involved with cellular movement. LRRC34 knockdown reduced the migration of thyroid cancer cell lines. Lastly, we assessed the relative contribution of PTC risk from each locus using haplotype analysis. CONCLUSIONS: Our study demonstrates two separate mechanisms, one in G protein signalling and the other in transcriptional control, dictating PTC risk at 3q26 using both biochemical and genetic techniques.

Co-occurrence of multiple endocrine neoplasia type 4 and spinal neurofibromatosis: a case report.

Multiple Endocrine Neoplasia (MEN) type 4 is a rare genetic condition that results from variants of the CDKN1B gene and predisposes individuals to develop endocrine tumors. Spinal neurofibromatosis (SNF) is an uncommon subtype of neurofibromatosis type 1 (NF1) characterized by bilateral neurofibromas of all spinal roots. Here we report a case of the co-occurrence of these syndromes, which has not yet been described in the literature. A male in his 60s presented with Gleason 5 + 4 localized prostate adenocarcinoma treated with radical prostatectomy. Two years later, he developed liver and bone metastasis consistent with trans-differentiation into small cell carcinoma. He developed hypercalcemia due to primary hyperparathyroidism from a parathyroid adenoma treated surgically. His family history was significant for a first-degree relative with a clinical diagnosis of NF1 and several second-degree relatives with multiple café-au-lait macules. Spine MRI showed multiple bilateral neurofibromas. Germline genetic testing showed a pathogenic variant in the CDKN1B gene, a variant in the NF1 gene, and a normal MEN1 gene. In this rare case of MEN4 and SNF, the patient was asymptomatic for much of his life. In addition to parathyroid adenoma and spinal neurofibromas, he had prostate adenocarcinoma with trans-differentiation into metastatic small cell cancer. Whether this diagnosis was coincidental or related to an emerging phenotype remains to be elucidated.

Thyroid Carcinomas That Occur in Familial Adenomatous Polyposis Patients Recurrently Harbor Somatic Variants in APC, BRAF, and KTM2D.

Background: Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the APC gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in APC is controversial. Methods: Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. Results: All 12 patients harbored germline mutations in APC, consistent with FAP. Seven patients also had somatic mutations in APC, and seven patients harbored somatic mutations in KMT2D, which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic BRAF p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in APC. Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Conclusions: Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in APC, which is associated with PTC-CMV histology. Somatic BRAF p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as APC, a cooperating second-hit somatic variant may occur in a different gene such as KTM2D or BRAF, leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.

A Truncating Germline Mutation of TINF2 in Individuals with Thyroid Cancer or Melanoma Results in Longer Telomeres.

Background: Our genome sequencing analysis revealed a frameshift mutation in the shelterin gene TINF2 in a large family with individuals affected with papillary thyroid carcinoma (PTC) and melanoma. Here, we further characterized the mutation and screened for coding variants in the 6 shelterin genes in 24 families. Methods: Sanger sequencing was performed to screen for the TINF2 mutation in the key family. Quantitative reverse transcription-polymerase chain reaction (PCR) was used for TINF2 gene expression analysis. Exogenous expression and co-immunoprecipitation techniques were used for assessing TINF2 binding to TERF1. Relative telomere length (RTL) was quantified in DNAs from lymphocytes by using quantitative real-time PCR. Whole exome sequencing (WES) was performed in seven families with individuals affected with PTC and other cancer types. Screening for DNA variants in shelterin genes was performed by using whole genome sequencing data from 17 families and WES data from 7 further families. Results: The TINF2 mutation (TINF2 p.Trp198fs) showed complete co-segregation with PTC and melanoma in the key family. The mutation is not reported in databases and not identified in 23 other families we screened. The expression of TINF2 was borderline reduced in individuals with the mutation. The truncated TINF2 protein showed abolished binding to TERF1. The RTL in the individuals with the mutation was significantly longer when compared with those without the mutation from the same family as well as compared with 62 healthy controls. Among the 24 families, we identified 3 missense and 1 synonymous variant(s) in 2 shelterin genes (TINF2 and ACD). Conclusions: The rare frameshift mutation in the TINF2 gene and the associated longer telomere length suggest that dysregulated telomeres could be a mechanism predisposing to PTC and melanoma. DNA coding variants in shelterin genes are rare. Further studies are required to evaluate the roles of variants in shelterin genes in thyroid cancer and melanoma.

Metastatic Adrenocortical Carcinoma: a Single Institutional Experience.

Adrenocortical carcinoma (ACC) is a rare malignancy with limited data to guide the management of metastatic disease. The optimal treatment strategies and outcomes of patients with metastatic ACC remain areas of active interest. We retrospectively reviewed patients with ACC who were treated with systemic therapy between January 1997 and October 2016 at The Ohio State University Comprehensive Cancer Center. Kaplan-Meier and Cox proportional hazards regression models were used for survival analysis. We identified 65 patients diagnosed with ACC during the given time period, and 36 patients received systemic therapy for distant metastatic disease. Median age at diagnosis was 50 (range 28-87). Median overall survival (OS) from time of diagnosis of ACC was 27 months (95% CI 19.6-39.3), and median OS from time of systemic treatment for metastatic disease was 18.7 months (95% CI 9.3-26.0). Clinical characteristics at time of initiation of systemic therapy were assessed, and presence of bone metastases (p = 0.66), ascites (p = 0.19), lung metastases (p = 0.12), liver metastases (p = 0.47), as well as hormonal activity of tumor (p = 0.19), were not prognostic for survival. Six patients with liver metastases treated with systemic therapy who received liver-directed therapy with either transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) had longer survival than those who did not (p = 0.011). Our data expands the knowledge of clinical characteristics and outcomes of patients with ACC and suggests a possible role for incorporating liver-directed therapies for patients with hepatic metastases.

Hypertrophic cardiomyopathy genetic test reports: A qualitative study of patient understanding of uninformative genetic test results.

Studies have shown that patients with hypertrophic cardiomyopathy (HCM) may misinterpret the meaning of uninformative genetic testing results to mean that a genetic etiology and family members' risk is ruled out. We hypothesized that poor comprehension of the laboratory genetic test report may contribute to this misunderstanding. We conducted a qualitative study to examine patient understanding of uninformative laboratory results and reports and elicit suggestions for an improved report. Fifteen participants with HCM were interviewed after undergoing genetic testing and receiving their report. While all patients read the report, most participants reported only partially reading it. Most reported not understanding the report at all or only partially understanding it because a provider explained it to them. Some participants said that the report was helpful for understanding their result, but there was evidence of misunderstanding; most participants stated that specific aspects of the report were unhelpful. While most of our participants communicated risk with relatives, none said that the report helped with the communication. Most participants did not recall or find the accompanying physician-directed result letter useful for their understanding or familial communication. Many participants expressed need for a supplemental report that illustrates a personalized clinical 'action plan' that could summarize clinical and familial implications of the result for the patient and their family. We conclude that laboratory reports and physician-directed result letters did not help participants understand their results or their familial implications. Our results suggest opportunities for research to explore the utility of a patient-directed result supplement to improve patient comprehension of genetic test results and outline clinical recommendations via a patient action plan.