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Biomedical subjects

William H Westra

Publications and source records attributed to William H Westra.

At least 19 recordsLinked to original sources
PubMed2006

Increased plasma DNA integrity index in head and neck cancer patients.

Analysis of the length of circulating DNA in plasma has been reported as a marker for solid tumor detection. We assessed the sensitivity and specificity of increased plasma DNA length to identify patients with head and neck squamous cell carcinoma (HNSCC) and monitor posttreatment disease status. Fifty-eight HNSCC patients with paired pre- and postoperative plasma and 47 plasma samples from control subjects were analyzed using quantitative PCR to determine plasma DNA integrity index. We found that the mean DNA integrity index was significantly greater in the plasma from HNSCC patients, 0.24 (95% CI: 0.11, 0.38), when compared to plasma from the control subjects, -2.24 (95% CI: -2.92, -1.56), p < 0.0001 using multivariate analysis. The optimal sensitivity (the value for which sensitivity equals specificity) was found at a plasma DNA integrity index of 0.82: sensitivity, 84.5%; specificity, 83%. However, there was no significant difference noted between pre- and postoperative DNA integrity index in plasma samples from HNSCC patients. This study shows that DNA integrity index in the plasma of the patients with HNSCC is increased in comparison with that in the plasma from non-HNSCC control subjects. Lack of normalization of plasma DNA integrity index after surgical resection implies the persistence of a population of cells with an altered pattern of DNA degradation despite removal of malignancy.

Adult↗
PubMed2006

Increased expression and activity of repair genes TDP1 and XPF in non-small cell lung cancer.

Resistance to camptothecin (CPT), a topoisomerase I (Top1) inhibitor, is frequently encountered in non-small cell lung cancer (NSCLC) and CPT resistance is linked with TDP1, an enzyme capable of cleaving the covalent linkage between stabilized Top1 with DNA. The aim of this study is to evaluate the in vivo expression level of TDP1, as well as parallel repair pathway components XPF and MUS81, in primary NSCLC. We collected 30 un-matched and 4 NSCLC samples matched with normal lung tissue and 8 samples of non-neoplastic lung tissue from patients with and without lung cancer, and determined the protein expression of these three genes using Western blot and TDP1 activity by a specific enzymatic assay. Both TDP1 and XPF were overexpressed in over 50% of NSCLC tissues, with wide ranges of expression levels. MUS81 did not exhibit alteration in expression. Overexpression of TDP1 and XPF is common in NSCLC, and is therefore of interest as a possible contributor to drug resistance in NSCLC.

Camptothecin↗
PubMed2006

Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer.

The role of aberrant tumor suppressor gene methylation in the aggressiveness of papillary thyroid cancer (PTC) has not been documented. By showing promoter methylation-induced gene silencing in PTC-derived cell lines, we first demonstrated the functional consequence of methylation of several recently identified tumor suppressor genes, including those for tissue inhibitor of metalloproteinase-3 (TIMP3), SLC5A8, death-associated protein kinase (DAPK) and retinoic acid receptor beta2 (RARbeta2). We then investigated the role of methylation of these genes in the aggressiveness of PTC by examining the relationship of their aberrant methylation to clinicopathological characteristics and BRAF mutation in 231 primary PTC tumors. Methylation of TIMP3, SLC5A8 and DAPK was significantly associated with several aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality and advanced tumor stages. Methylation of these genes was also significantly associated with BRAF mutation in PTC, either individually or collectively in various combinations. Methylation of these genes, either individually or collectively, occurred more frequently in more aggressive classical and tall-cell PTC subtypes than in less aggressive follicular-variant PTC, with the latter known to infrequently harbor BRAF mutation. Several other tumor suppressor genes investigated were not methylated. These results suggest that aberrant methylation and hence silencing of TIMP3, SLC5A8, DAPK and RARbeta2, in association with BRAF mutation, may be an important step in PTC tumorigenesis and progression.

Apoptosis Regulatory Proteins↗
PubMed2006

Genome-wide expression profiling reveals EBV-associated inhibition of MHC class I expression in nasopharyngeal carcinoma.

To identify the molecular mechanisms by which EBV-associated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogene-mediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC.

Biopsy↗
PubMed2006

Quantitation of promoter methylation of multiple genes in urine DNA and bladder cancer detection.

BACKGROUND: The noninvasive identification of bladder tumors may improve disease control and prevent disease progression. Aberrant promoter methylation (i.e., hypermethylation) is a major mechanism for silencing tumor suppressor genes and other cancer-associated genes in many human cancers, including bladder cancer. METHODS: A quantitative fluorogenic real-time polymerase chain reaction (PCR) assay was used to examine primary tumor DNA and urine sediment DNA from 15 patients with bladder cancer and 25 control subjects for promoter hypermethylation of nine genes (APC, ARF, CDH1, GSTP1, MGMT, CDKN2A, RARbeta2, RASSF1A, and TIMP3) to identify potential biomarkers for bladder cancer. We then used these markers to examine urine sediment DNA samples from an additional 160 patients with bladder cancers of various stages and grades and from an additional 69 age-matched control subjects. Data were analyzed on the basis of a prediction model and were internally validated using a jacknife procedure. All statistical tests were two-sided. RESULTS: For all 15 patients with paired DNA samples, the promoter methylation pattern in urine matched that in the primary tumors. Four genes displayed 100% specificity. Of the 175 bladder cancer patients, 121 (69%, 95% confidence interval [CI] = 62% to 76%) displayed promoter methylation in at least one of these genes (CDKN2A, ARF, MGMT, and GSTP1), whereas all control subjects were negative for such methylation (100% specificity, 95% CI = 96% to 100%). A logistic prediction model using the methylation levels of all remaining five genes was developed and internally validated for subjects who were negative on the four-gene panel. This combined, two-stage predictor produced an internally validated ROC curve with an overall sensitivity of 82% (95% CI = 75 % to 87%) and specificity of 96% (95% CI = 90% to 99%). CONCLUSION: Testing a small panel of genes with the quantitative methylation-specific PCR assay in urine sediment DNA is a powerful noninvasive approach for the detection of bladder cancer. Larger independent confirmatory cohorts with longitudinal follow-up will be required in future studies to define the impact of this technology on early detection, prognosis, and disease monitoring before clinical application.

Aged↗
PubMed2006

Decreased mitochondrial DNA content in posttreatment salivary rinses from head and neck cancer patients.

PURPOSE AND EXPERIMENTAL DESIGN: Alterations in mitochondrial DNA (mtDNA) sequence and content have been described in human tissues and tumors in association with smoking exposure. We did quantitative PCR analysis of cytochrome c oxidase (Cox) I and Cox II genes to measure changes in mtDNA content in pretreatment and posttreatment salivary rinses obtained from 76 patients undergoing surgical resection for primary head and neck squamous cell carcinoma. We also examined the relationship between changes in mtDNA content and postoperative radiation therapy, smoking exposure, alcohol intake, and other clinical characteristics. RESULTS: Overall, mtDNA content in posttreatment saliva was significantly decreased. The mean change for Cox I was -0.21 [95% confidence interval (95% CI), -0.44 to 0.01, P = 0.06] and for Cox II was -0.31 (95% CI, -0.55 to -0.08, P = 0.01). Patients in the radiation therapy group exhibited a significant decrease compared with the nonradiated group (P = 0.03 for Cox I; P = 0.05 for Cox II). In addition, significant decreases in Cox I (-0.71; 95% CI, -1.17 to -0.25, P = 0.005) and Cox II (-0.65; 95% CI, -1.17 to -0.13, P = 0.02) were found in never-smoking patients but not in former or current smokers. CONCLUSION: Our data suggest that salivary mtDNA content is decreased in never smokers and in response to radiation therapy after primary surgical resection.

Adult↗
PubMed2006

Cytopathologic analysis of thyroid lesions in the pediatric population.

Fine-needle aspiration (FNA) of the thyroid is seldom performed in the pediatric population. Therefore, the clinical utility of thyroid FNA in this patient group has not been adequately addressed. A 15 yr retrospective review of the cytopathology archives at the participating institutions was performed to identify cases of thyroid FNA performed in pediatric patients. The medical records of these cases were reviewed, including the surgical pathology reports of those patients who had subsequently undergone surgical resection. One hundred one specimens from 82 patients were identified. Of these, 40 had a cytopathologic diagnosis of carcinoma, "suspicious" for carcinoma, neoplasm, or atypia, 48 were benign, and 13 were unsatisfactory. Of the 82 patients, 45 underwent partial or total thyroidectomy. Twenty-two (49%) of these were found to harbor a malignant neoplasm (18 papillary carcinomas). The diagnostic sensitivity for identifying a lesion was 87% (26/30) and the diagnostic specificity was 92% (47/51). There were four false-positives and four false-negatives in the review, yielding a positive predictive value of 87% and a negative predictive value of 92%. We conclude that FNA is a useful adjunct to the management of thyroid lesions in the pediatric population, with good diagnostic accuracy. Although thyroid neoplasms are relatively rare in children, our experience demonstrated that 40% of thyroid masses referred for FNA had an interpretation that caused concern, ranging from "atypical" to carcinoma. Additionally, a benign diagnosis by FNA may avoid unnecessary surgery with its potential complications, a significant consideration for this age group.

Adolescent↗
PubMed2006

The role of fine needle aspiration in the evaluation of parotid masses.

PURPOSE OF REVIEW: Fine needle aspiration is a safe diagnostic technique that is widely employed for lesions of the head and neck. Among head and neck sites, the parotid gland stands apart for the number, diversity and peculiarity of pathologic processes to target this structure. This matchless complexity has prompted a thoughtful discussion regarding the application of the fine needle aspiration to parotid masses--a discussion that has primarily focused on the reliability of the fine needle aspiration as a diagnostic tool, and on its utility in guiding patient management. RECENT FINDINGS: Recent studies have confirmed a high overall accuracy rate for fine needle aspiration evaluation of parotid masses, ranging from 90 to 95%. At the same time, these soaring accuracy rates cannot be uniformly anticipated across all diagnostic scenarios. Fine needle aspiration is notoriously unreliable in recognizing the malignant nature of the parotid carcinoma, providing its precise classification, and establishing its grade. A few malignant neoplasms are particularly prone to diagnostic error. Acinic cell carcinoma is frequently interpreted as benign or even nonneoplastic; and low-grade lymphomas are often discounted as inflammatory processes. SUMMARY: Parotid gland masses are not particularly conducive to diagnostic accuracy and precision by fine needle aspiration. Accordingly, indiscriminant reliance on the fine needle aspiration findings at the expense of the clinical, radiographic, and intraoperative findings is unwarranted. Whether one uses the fine needle aspiration routinely or selectively in patients with parotid masses, the fine needle aspiration findings should contribute to, not displace, the overall diagnostic impression.

Biopsy, Fine-Needle↗
PubMed2005

Quantitative methylation-specific polymerase chain reaction gene patterns in urine sediment distinguish prostate cancer patients from control subjects.

PURPOSE: Aberrant promoter hypermethylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of prostate cancers and is a promising marker for cancer detection. We sought to develop a test for prostate cancer based on a quantitative methylation-specific polymerase chain reaction (QMSP) of multiple genes in urine sediment DNA. PATIENTS AND METHODS: We tested urine sediment DNA for aberrant methylation of nine gene promoters (p16INK4a, p14(ARF), MGMT, GSTP1, RARbeta2, CDH1 [E-cadherin], TIMP3, Rassf1A, and APC) from 52 patients with prostate cancer and 21 matched primary tumors by quantitative fluorogenic real-time polymerase chain reaction. We also analyzed urine sediments from 91 age-matched individuals without any history of genitourinary malignancy as controls. RESULTS: Promoter hypermethylation of at least one of the genes studied was detected in urine samples from all 52 prostate cancer patients. Urine samples from the 91 controls without evidence of genitourinary cancer revealed no methylation of the p16, ARF, MGMT, and GSTP1 gene promoters, whereas methylation of RARbeta2, TIMP3, CDH1, Rassf1A, and APC was detected at low levels. CONCLUSION: Overall, methylation found in urine samples matched the methylation status in the primary tumor. A combination of only four genes (p16, ARF, MGMT, and GSTP1) would theoretically allow us to detect 87% of prostate cancers with 100% specificity. Our data support further development of the noninvasive QMSP assay in urine DNA for early detection and surveillance of prostate cancer.

Adult↗
PubMed2005

BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer.

CONTEXT: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. OBJECTIVE: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. DESIGN, SETTING, AND SUBJECTS: In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. MAIN OUTCOME MEASURE: Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. RESULTS: We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjusting for conventional clinicopathological predictors of recurrence excluding the histological PTC subtype, but was lost when the tumor subtype was included in the model. BRAF mutation was also significantly associated with tumor recurrence, 25 vs. 9% with and without mutation, respectively (P = 0.004), during a median of 15 (interquartile range, 3-29) months of follow-up. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence, even including the PTC subtype (odds ratio, 4.0; 95% confidence interval, 1.1-14.1; P = 0.03). BRAF mutation was even an independent predictor of recurrence in patients with stage I/II disease, 22 vs. 5% with and without BRAF mutation, respectively (P = 0.002). BRAF mutation was also more frequently associated with absence of tumor I-131 avidity and treatment failure of recurrent disease. CONCLUSIONS: In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.

Adult↗
PubMed2005

Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma.

PURPOSE: Human papillomavirus 16 (HPV-16) has been implicated as a causative agent in a subset of head and neck squamous cell carcinomas (HNSCC). This study was undertaken to discern the distribution and timing of HPV viral integration during tumorigenesis of the upper respiratory tract. EXPERIMENTAL DESIGN: A tissue array was assembled from a consecutive group of 176 patients with HNSCCs. The array was evaluated by HPV-16 in situ hybridization and p16 immunohistochemistry. Patients with HPV-positive tonsillar cancers who had undergone bilateral tonsillectomies were selected for more complete mapping of viral integration. RESULTS: HPV-16 was detected in 38 of the 176 (22%) cases by in situ hybridization. When stratified by site of origin, HPV-16 was detected in 37 of 45 cancers arising from the oropharynx but in only 1 of 131 tumors arising from nonoropharyngeal sites (82% versus 0.8%, P < 0.00001). P16 expression was associated with the presence of HPV-16: 31 of 38 HPV-positive tumors exhibited p16 expression, whereas only 9 of the 138 HPV-negative tumors were p16-positive (82% versus 6%, P < 0.00001). In the bilateral tonsil sections, hybridization signals were strictly limited to the invasive cancers and associated dysplasias. P16 staining was widely distributed throughout the nonneoplastic crypt epithelium of individuals with and without tonsillar cancer. CONCLUSIONS: HPV-16 is strongly associated with carcinomas arising from the oropharynx, and integration is tightly coupled to the neoplastic process. Viral integration does not occur as a field alteration throughout normal tonsillar epithelium. P16 expression localizes to HPV-positive cancers, and is intrinsic to the specialized epithelium of the tonsillar crypts. For risk assessment, early cancer detection and disease surveillance, evidence of HPV-16 integration may represent a meaningful finding, whereas high p16 expression, by itself, may not.

Carcinoma, Squamous Cell↗
PubMed2005

Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma is frequently multifocal. We investigated whether noncontiguous tumor foci arise from intraglandular metastases from a single primary tumor or originate as unrelated clones derived from independent precursors. METHODS: Using a polymerase-chain-reaction assay involving the human androgen receptor gene (HUMARA), we analyzed the patterns of X-chromosome inactivation of multiple distinct foci of well-differentiated multifocal papillary thyroid cancer from 17 women. RESULTS: Multiple thyroid tumor foci from 10 of 17 patients yielded DNA of adequate quality and were heterozygous for the HUMARA polymorphism and hence suitable for analysis. A single X chromosome was inactivated in each focus, consistent with its monoclonality. When the specific monoclonal configurations of each patient's discrete tumor foci were compared, discordant patterns indicative of independent origins were observed among the tumors from five patients; results in the remaining five were consistent with either a shared or independent clonal origin. CONCLUSIONS: Individual tumor foci in patients with multifocal papillary thyroid cancer often arise as independent tumors.

Carcinoma, Papillary↗
PubMed2005

Increased mitochondrial DNA content in saliva associated with head and neck cancer.

Alterations of the mitochondrial DNA (mtDNA) have been described in human tumors and in other tissues in association with smoking exposure. We did quantitative PCR of cytochrome c oxidase I (Cox I) and cytochrome c oxidase II (Cox II) genes on oral rinse samples obtained from 94 patients with primary head and neck squamous cell carcinoma (HNSC) and a control group of 656 subjects. Mitochondrial DNA/nuclear DNA in saliva from HNSC patients and controls in relationship to smoking exposure, ethanol intake, and tumor stage were examined. Mean levels of Cox I and Cox II in saliva samples were significantly higher in HNSC patients: Cox I, 0.076 [95% confidence interval (95% CI), 0.06-0.09] and Cox II, 0.055 (95% CI, 0.04-0.07) in comparison with controls Cox I, 0.054 (95% CI, 0.05-0.06), P < 0.0001 and Cox II, 0.046 (95% CI, 0.04-0.05), P = 0.003 (t test). MtDNA levels were elevated in primary tumors when compared with matched, pretreatment saliva and significant correlation was noted (Cox I, r = 0.30, P = 0.005 and Cox II r = 0.33, P = 0.002, respectively, Pearson's correlation). On univariate analysis, smoking, age, HNSC diagnosis, and advanced stage of HNSC were associated with higher level of mtDNA content in saliva. Multivariate analysis showed a significant and independent association of HNSC diagnosis, age, and smoking with increasing mtDNA/nuclear DNA for Cox I and Cox II. mtDNA content alteration is associated with HNSC independently of age and smoking exposure, can be detected in saliva, and may be due to elevation in mtDNA content in primary HNSC.

Adolescent↗
PubMed2005

Molecular margin analysis predicts local recurrence after sublobar resection of lung cancer.

Sublobar resection for early-stage lung cancer has been used for patients who are not candidates for lobar resection. However, sublobar resection is associated with high local recurrence rates in the context of tumor-free parenchymal margins. The mechanism underlying this high recurrence rate is not well understood. We hypothesized that this elevated risk of local recurrence is due to undetected tumor cells present at parenchymal margins thought to be negative by conventional light microscopy. Thirteen of 44 patients who underwent sublobar resection for lung cancer were found to have a k-ras mutation at codon 12.1. A novel fluorescence-based assay for detection of rare copies of mutant DNA in a background of wild-type DNA, fluorescent gap ligase chain reaction, was used to quantitate the mutant/wild-type DNA in a range of 1 to 1/10,000 in histologically normal margins from these resections. Nine of 13 patients had at least one margin with the number of mutant cells over or equal to a threshold of 1/5,000, and of these, 6/9 (67%) recurred locally. None of the remaining 4 patients without mutant DNA in any surgical margin had evidence of recurrence. The higher rate of local recurrence associated with sublobar resection of lung cancer is likely due to the occult presence of tumor cells at resection margins. These occult tumor cells can be quantitated using a novel fluorescence-based assay and define a group of patients at high risk for local recurrence who are candidates for adjuvant therapy or more extensive resection. This methodology may be adaptable to a real-time format for intraoperative use.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Absence of V599E BRAF mutations in desmoplastic melanomas.

BACKGROUND: Desmoplastic melanoma is an uncommon variant of cutaneous melanoma that mimics soft tissue sarcoma both clinically and morphologically. An activating point mutation of the BRAF oncogene has been identified in a high proportion of conventional cutaneous melanomas, but its frequency in the desmoplastic subtype is not known. METHODS: The authors tested 12 desmoplastic melanoma specimens for the thymine (T)-->adenine (A) missense mutation at nucleotide 1796 of the BRAF gene using a newly developed assay that employs a novel primer extension method. They also tested 57 vertical growth phase cutaneous nondesmoplastic melanoma specimens. RESULTS: The 1796 T-->A mutation was detected in 23 of the 57 conventional cutaneous melanoma specimens but in none of the 12 desmoplastic melanoma specimens (40% vs. 0%; P=0.0006, Fisher exact 2-tailed test). CONCLUSIONS: The relative importance of BRAF mutational activation in melanocytic tumorigenesis clearly was not the same across the various subtypes of melanoma, even for melanomas of cutaneous origin that are associated with sun exposure. In contrast to conventional cutaneous melanomas, the desmoplastic variant frequently did not harbor an activating mutation of BRAF. Accordingly, patients with melanomas should not be collectively regarded as a uniform group as new therapeutic strategies are developed that target specific genetic alterations.

Female↗
PubMed2005

DeltaNp63alpha up-regulates the Hsp70 gene in human cancer.

HSP70, a stress response protein, is known to be a determinant of cell death and cell transformation. We show that different isoforms of p63 have different transcriptional activities on hsp70 genes. DeltaNp63alpha, an abundantly expressed isoform of p63, activates (in vitro and in vivo), whereas TAp63gamma down-regulates the expression of hsp70. We further show that the transactivation domain at the NH(2) terminus of p63 represses, whereas the COOH terminus activates hsp70 transcription. In addition, DeltaNp63alpha regulates transcription of the hsp70 gene through its interaction with the CCAAT binding factor and NF-Y transcription factors which are known to form a complex with the CCAAT box located in the hsp70 promoter. Moreover, DeltaNp63alpha expression correlates with HSP70 expression in all head and neck cancer cell lines. Finally, we show colocalization of DeltaNp63alpha and HSP70 in the epithelium and coexpression of both proteins in 41 primary head and neck cancers. Our study provides strong evidence for the physiologic association between DeltaNp63alpha and hsp70 in human cancer, thus further supporting the oncogenic potential of DeltaNp63alpha.

Animals↗
PubMed2005

Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma.

Papillary thyroid carcinoma may encompass a mixed group of neoplasms where divergence in clinical behavior may reflect distinct genetic alterations. For example, young patients with papillary thyroid carcinoma have a better prognosis than affected adults, and their carcinomas are much more likely to harbor chromosomal rearrangements involving the RET proto-oncogene. Mutational activation of the BRAF oncogene has recently been identified as the most common genetic alteration in papillary thyroid carcinoma, but little is known about its frequency as a function of patient age. We tested 20 papillary thyroid carcinomas from young patients ranging from 10 to 17 years of age for the thymine (T) --> adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector assay). The prevalence of BRAF mutation was compared with a larger group of papillary thyroid carcinomas from previously tested adult patients (>20 years). BRAF mutations were not common in papillary thyroid carcinomas from young patients compared to their counterparts in adults (20 vs 77%; OR=13.3, 95% confidence interval (CI)=3.4-56.5; P<0.0001), but they become increasingly prevalent with advancing patient age (OR as a function of age at 10-year intervals=1.80 CI=1.33-2.44; P<0.001). Unlike papillary thyroid carcinomas that arise in adults, mutational activation of BRAF is not a major genetic alteration in papillary thyroid carcinomas that arise in young patients. The increasing frequency of BRAF mutations as a function of age could help account for the well documented but poorly understood observation that age is a relevant prognostic indicator for patients with papillary thyroid carcinoma.

Adolescent↗