Sharon A. Savage

Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the Surveillance, Epidemiology, and End Results Program

Osteosarcoma, which is the most common primary bone tumor, occurs most frequently in adolescents, but there is a second incidence peak among individuals aged >60 years. Most osteosarcoma epidemiology studies have been embedded in large analyses of all bone tumors or focused on cases occurring in adolescence. Detailed descriptions of osteosarcoma incidence and survival with direct comparisons among patients of all ages and ethnicities are not available.

A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.

TINF2, a Component of the Shelterin Telomere Protection Complex, Is Mutated in Dyskeratosis Congenita

Patients with dyskeratosis congenita (DC), a heterogeneous inherited bone marrow failure syndrome, have abnormalities in telomere biology, including very short telomeres and germline mutations in DKC1, TERC, TERT, or NOP10, but approximately 60% of DC patients lack an identifiable mutation. With the very short telomere phenotype and a highly penetrant, rare disease model, a linkage scan was performed on a family with autosomal-dominant DC and no mutations in DKCI, TERC, or TERT. Evidence favoring linkage was found at 2p24 and 14q11.2, and this led to the identification of TINF2 (14q11.2) mutations, K280E, in the proband and her five affected relatives and TINF2 R282H in three additional unrelated DC probands, including one with Revesz syndrome; a fifth DC proband had a R282S mutation. TINF2 mutations were not present in unaffected relatives, DC probands with mutations in DKC1, TERC, or TERT or 298 control subjects. We demonstrate that a fifth gene, TINF2, is mutated in classical DC and, for the first time, in Revesz syndrome. This represents the first shelterin complex mutation linked to human disease and confirms the role of very short telomeres as a diagnostic test for DC.

Cancer in dyskeratosis congenita

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome. The spectrum of cancer susceptibility in this disorder of telomere biology has not been described. There were more than 500 cases of DC reported in the literature from 1910 to 2008; the National Cancer Institute (NCI) prospective DC cohort enrolled 50 cases from 2002 to 2007. Sixty cancers were reported in 52 literature cases, while 7 occurred among patients in the NCI DC cohort. The 2 cohorts were comparable in their median overall survival (42 years) and cumulative incidence of cancer (40%-50% by age 50 years). The most frequent solid tumors were head and neck squamous cell carcinomas (40% of patients in either cohort), followed by skin and anorectal cancer. The ratio of observed to expected cancers (O/E ratio) in the NCI cohort was 11-fold compared with the general population (P < .05). Significantly elevated O/E ratios were 1154 for tongue cancer and 195 for acute myeloid leukemia. Survival after bone marrow transplantation for aplastic anemia or leukemia was poor in both cohorts. The frequency and types of cancer in DC are surpassed only by those in Fanconi anemia (FA), indicating that FA and DC have similarly high risks of adverse hematologic and neoplastic events, and patients with these diseases should be counseled and monitored similarly.

The Association of Telomere Length and Cancer: A Meta-Analysis

Background: Telomeres shorten with each cell division and are essential for chromosomal stability. Short telomeres in surrogate tissues (e.g., blood cells) are associated with increased cancer risk in several case–control studies, but findings are inconsistent in prospective studies. Methods: We systematically reviewed studies published prior to August 30, 2010, on the association between telomere length (TL) in surrogate tissues and cancer. There were 27 reports on 13 cancers and/or incident cancer investigating this association. The majority, 16, were retrospective case–control studies, 11 were prospective studies. Meta-analyses were conducted to determine ORs and 95% CIs for these studies. Results: Studies on bladder, esophageal, gastric, head and neck, ovarian, renal, and overall incident cancer found associations between short telomeres and these cancers. Non–Hodgkin lymphoma, breast, lung, and colorectal cancer reports were inconsistent. Single studies on endometrial, prostate, and skin cancers were null. In a random-effects meta-analysis, short TL was significantly associated with cancer in retrospective studies (pooled OR for the shortest TL quartile compared with the longest: 2.9, 95% CI: 1.75–4.8, P < 0.0001). The pooled OR for prospective studies was 1.16 (95% CI: 0.87–1.54, P = 0.32). All studies combined yielded a pooled OR of 1.96 (95% CI: 1.37–2.81, P = 0.0001) for the association of short TL and cancer. Conclusion and Impact: There is suggestive evidence that short surrogate tissue TL is associated with cancer; the strongest evidence exists for bladder, esophageal, gastric, and renal cancers. Additional prospective studies with consistent methodology are needed to confirm this hypothesis. Cancer Epidemiol Biomarkers Prev; 20(6); 1238–50. ©2011 AACR.

Rating the methodological quality of single-subject designs and n-of-1 trials: Introducing the Single-Case Experimental Design (SCED) Scale

Rating scales that assess methodological quality of clinical trials provide a means to critically appraise the literature. Scales are currently available to rate randomised and non-randomised controlled trials, but there are none that assess single-subject designs. The Single-Case Experimental Design (SCED) Scale was developed for this purpose and evaluated for reliability. Six clinical researchers who were trained and experienced in rating methodological quality of clinical trials developed the scale and participated in reliability studies. The SCED Scale is an 11-item rating scale for single-subject designs, of which 10 items are used to assess methodological quality and use of statistical analysis. The scale was developed and refined over a 3-year period. Content validity was addressed by identifying items to reduce the main sources of bias in single-case methodology as stipulated by authorities in the field, which were empirically tested against 85 published reports. Inter-rater reliability was assessed using a random sample of 20/312 single-subject reports archived in the Psychological Database of Brain Impairment Treatment Efficacy (PsycBITETM). Inter-rater reliability for the total score was excellent, both for individual raters (overall ICC = 0.84; 95% confidence interval 0.73–0.92) and for consensus ratings between pairs of raters (overall ICC = 0.88; 95% confidence interval 0.78–0.95). Item reliability was fair to excellent for consensus ratings between pairs of raters (range k = 0.48 to 1.00). The results were replicated with two independent novice raters who were trained in the use of the scale (ICC = 0.88, 95% confidence interval 0.73–0.95). The SCED Scale thus provides a brief and valid evaluation of methodological quality of single-subject designs, with the total score demonstrating excellent inter-rater reliability using both individual and consensus ratings. Items from the scale can also be used as a checklist in the design, reporting and critical appraisal of single-subject designs, thereby assisting to improve standards of single-case methodology.

Subtypes of progressive aphasia: application of the international consensus criteria and validation using β-amyloid imaging

Primary progressive aphasia comprises a heterogeneous group of neurodegenerative conditions with diverse clinical profiles and underlying pathological substrates. A major development has been the publication of the recent International Consensus Criteria for the three major variants namely: semantic, non-fluent/agrammatic and logopenic. The logopenic variant is assumed to represent an atypical presentation of Alzheimer pathology although evidence for this is, at present, limited. The semantic and non-fluent/agrammatic variants are largely associated with frontotemporal lobar degeneration with TDP-43 and tau pathology, respectively. The applicability of the International Consensus Criteria to an unselected clinical sample is unknown and no agreed clinical evaluation scale on which to derive the diagnosis exists. We assessed 47 consecutive cases of primary progressive aphasic seen over a 3-year period in a specialist centre, using a newly developed progressive aphasia language scale. A subgroup of 30 cases underwent (11)C-labelled Pittsburgh Compound B positron emission tomography imaging, a putative biomarker of Alzheimers disease that detects β-amyloid accumulation, and they were compared with an age-matched group (n = 10) with typical, predominately amnestic Alzheimers disease. The application of an algorithm based on four key speech and language variables (motor speech disorders, agrammatism, single-word comprehension and sentence repetition) classified 45 of 47 (96%) of patients and showed high concordance with the gold standard expert clinical diagnosis based on the International Consensus Criteria. The level of neocortical β-amyloid burden varied considerably across aphasic variants. Of 13 logopenic patients, 12 (92%) had positive β-amyloid uptake. In contrast, one of nine (11%) semantic variant and two of eight (25%) non-fluent/agrammatic cases were positive. The distribution of β-amyloid across cortical regions of interest was identical in cases with the logopenic variant to that of patients with typical Alzheimers disease although the total load was lower in the aphasic cases. Impairments of sentence repetition and sentence comprehension were positively correlated with neocortical burden of β-amyloid, whereas impaired single-word comprehension showed a negative correlation. The International Consensus Criteria can be applied to the majority of cases with primary progressive aphasic using a simple speech and language assessment scale based upon four key variables. β-amyloid imaging confirms the higher rate of Alzheimer pathology in the logopenic variant and, in turn, the low rates in the other two variants. The study offers insight into the biological basis of clinical manifestations of Alzheimers disease, which appear topographically independent of β-amyloid load.

Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study.

Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond‐Blackfan anaemia (DBA), and Shwachman‐Diamond syndrome (SDS) comprise major inherited bone marrow failure syndromes (IBMFS). Adverse events include severe bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid tumours (ST). The natural history of FA is well characterised; hazard rates in the other syndromes have not yet been quantified. An open cohort was established at the National Cancer Institute (NCI) in 2002. Patients enrolled prior to December, 2007 were followed up to December, 2008. Diagnoses were confirmed with standard tests. Age‐associated risks of adverse events were calculated. Most patients in each syndrome survived to young adulthood. Patients with FA had earlier onset of cancers, need for stem cell transplant, and death; followed by DC; DBA and SDS were mildest. While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients. The NCI cohort provides the first direct quantitative comparison of timing and magnitude of cancer risk in the IBMFS. The findings demonstrate that both FA and DC are major cancer susceptibility syndromes. The IBMFS, historically considered paediatric disorders, have important management implications for physicians treating adult patients.

International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons†

Osteosarcoma incidence rates in the United States peak in adolescence and in the elderly. The international patterns of osteosarcoma incidence in children have been described, whereas those for young, middle age or elderly adults have not. Using the Cancer Incidence in Five Continents, International Agency for Cancer Research database we compared incidence rates for children and adolescents (age 0–24 years), the middle age group (25–59 years) and elderly (≥60 years) persons by world regions and individual countries. Overall, worldwide osteosarcoma incidence rates were quite similar in the younger age groups. The greatest variation in incidence rates was observed in the elderly. Published 2009 UICC

Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells

The differentiation of patient-derived induced pluripotent stem cells (iPSCs) to committed fates such as neurons, muscle and liver is a powerful approach for understanding key parameters of human development and disease. Whether undifferentiated iPSCs themselves can be used to probe disease mechanisms is uncertain. Dyskeratosis congenita is characterized by defective maintenance of blood, pulmonary tissue and epidermal tissues and is caused by mutations in genes controlling telomere homeostasis. Short telomeres, a hallmark of dyskeratosis congenita, impair tissue stem cell function in mouse models, indicating that a tissue stem cell defect may underlie the pathophysiology of dyskeratosis congenita. Here we show that even in the undifferentiated state, iPSCs from dyskeratosis congenita patients harbour the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, because telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. These findings in iPSCs from dyskeratosis congenita patients reveal that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell-culture-based system for the development of targeted therapeutics.