Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma.

INTRODUCTION: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma. METHODS: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene. RESULTS: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma. CONCLUSION: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.

Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19.

Introduction: Diamond Blackfan anemia (DBA) is an autosomal dominant ribosomopathy caused predominantly by pathogenic germline variants in ribosomal protein genes. It is characterized by failure of red blood cell production, and common features include congenital malformations and cancer predisposition. Mainstays of treatment are corticosteroids, red blood cell transfusions, and hematologic stem cell transplantation (HSCT). Despite a better understanding of the genotype of DBA, the biological mechanism resulting in the clinical phenotype remains poorly understood, and wide heterogeneity can be seen even within a single family as depicted here. Case Description: Thirty family members enrolled in the National Cancer Institute inherited bone marrow failure syndromes study were evaluated with detailed medical questionnaires and physical examinations, including 22 in the family bloodline and eight unrelated partners. Eight participants had been previously told they had DBA by clinical criteria. Targeted germline RPS19 testing was done on all family members. A pathogenic heterozygous missense mutation in RPS19 (p.R62Q, c.185G > A) was detected in ten family members, including one person previously presumed unaffected. Eight family members presented with macrocytic anemia in infancy; all of whom were responsive to prednisone. Four family members became treatment independent; however, one individual became transfusion-dependent 36 years later following an episode of pneumonia. One prednisone responsive individual electively discontinued steroid treatment, and lives with severe anemia. One prednisone responsive individual died at age 28 from a stroke. Two family members developed colorectal cancer in their fifties; one had never required treatment for anemia. None had major congenital anomalies. Discussion: This large family with DBA demonstrates the heterogeneity of phenotypes that can be seen within the same genotype. Most family members presented with steroid-responsive anemia in infancy and subtle congenital malformations, findings consistent with recent genotype-phenotype studies of RPS DBA. However, two family members were relatively unaffected, underscoring the importance of further studies to assess modifier genes, and epigenetic and/or environmental factors which may result in normal erythropoiesis despite underlying ribosome dysfunction. This large, multigenerational family highlights the need for individualized treatment, the importance of early cancer surveillance even in individuals with clinically mild phenotypes, and the benefit of long-term follow-up to identify late complications.

Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.

BACKGROUND AND OBJECTIVES: Shwachman Diamond syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) associated with pancreatic insufficiency, neutropenia, and skeletal dysplasia. Biallelic pathogenic variants (PV) in SBDS account for >90% of SDS. We hypothesized that the SDS phenotype varies based on genotype and conducted a genotype-phenotype correlation study to better understand these complexities. METHODS: We reviewed records of all patients with SDS or SDS-like syndromes in the National Cancer Institute's (NCI) IBMFS study. Additional published SDS cohorts were reviewed and compared with the NCI cohort. RESULTS: PVs in SBDS were present in 32/47 (68.1%) participants. Biallelic inheritance of SBDS c.258 + 2T > C and c.183_184TA > CT was the most common genotype in our study (25/32, 78.1%) and published cohorts. Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%). Developmental delay was common (20/34, 58.8%). Increased risk of hematologic malignancies at young ages and the rarity of solid malignancies was observed in both the NCI cohort and published studies. CONCLUSIONS: SDS is a complex childhood illness with a narrow genotypic spectrum. Patients may first present to primary care, gastroenterology, orthopedic, and/or hematology clinics. Coordinated multidisciplinary care is important for diagnosis and patient management. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00027274. IMPACT: The clinical and genetic spectrum of Shwachman Diamond Syndrome was comprehensively evaluated, and the findings illustrate the importance of a multidisciplinary approach for these complex patients. Our work reveals: 1. a narrow genotypic spectrum in SDS; 2. a low risk of solid tumors in patients with SDS; 3. patients with SDS have clinical manifestations in multiple organ systems.

Osteosarcoma: A Surveillance, Epidemiology, and End Results program-based analysis from 1975 to 2017.

BACKGROUND: Osteosarcoma is the most common primary bone malignancy. As a rare cancer, population-based studies remain small with limited information on finer demographic categories. Recent studies have reported important genetic differences based on age and ethnicity, and more detailed studies are needed to better understand potentially important osteosarcoma risk groups. METHODS: Incidence and survival rates for 5016 patients with osteosarcoma from the Surveillance, Epidemiology, and End Results (SEER) program (1975-2017) were analyzed by age (0-9, 10-24, 25-59, and >60 years old), race/ethnicity, histologic subtype, stage, and tumor location using SEER*Stat software. RESULTS: For cases 0 to 9 years old, incidence of primary osteosarcoma was similar between the sexes, increased significantly throughout the study period (P < .05), and the 5-year relative survival has steadily increased over time. Blacks had the highest incidence in all aged cases combined and a significant increase in incidence throughout the study period (P < .05). Overall, survival rates for all cases have remained relatively unchanged over recent decades, with worse survival observed in males, American Indian/Alaska Native cases, older patients, metastatic disease, axial tumors, and subsequent osteosarcoma cases. For cases 0 to 24 years old, the incidence of subsequent osteosarcoma increased 3-fold since the 2000s. CONCLUSION: Important differences in osteosarcoma incidence and survival, particularly for the youngest children, ethnic minorities, and subsequent osteosarcoma, are identified. A genetic risk factor may be associated with observed ancestry-specific incidence differences and illustrates the importance of analyzing osteosarcoma by specific age groups and ethnicities to better understand their unique epidemiology and underlying biology. LAY SUMMARY: Osteosarcoma is the most common bone cancer, but still a relatively rare disease, and previous studies have had limited information on finer demographics. Using a large database, osteosarcoma incidence and survival patterns are thoroughly evaluated and important differences, especially for the youngest children, ethnic minorities, and subsequent osteosarcoma cases, are identified.

Whole-exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with variable expression and nearly complete penetrance. PTCH1 is the major susceptibility locus and has no known hot spots or genotype-phenotype relationships. METHODS: We evaluated 18 NBCCS National Cancer Institute (NCI) families plus PTCH1 data on 333 NBCCS disease-causing mutations (DM) reported in the Human Gene Mutation Database (HGMD). National Cancer Institute families underwent comprehensive genomic evaluation, and clinical data were extracted from NCI and HGMD cases. Genotype-phenotype relationships were analyzed using Fisher's exact tests focusing on mutation type and PTCH1 domains. RESULTS: PTCH1 pathogenic mutations were identified in 16 of 18 NCI families, including three previously mutation-negative families. PTCH1 mutations were spread across the gene with no hot spot. After adjustment for multiple tests, a statistically significant genotype-phenotype association was observed for developmental delay and gross deletion-insertions (p = 9.0 × 10-6 ), and suggestive associations between falx cerebri calcification and all transmembrane domains (p = 0.002) and severe outcomes and gross deletion-insertions (p = 4.0 × 10-4 ). CONCLUSION: Overall, 89% of our NCI families had a pathogenic PTCH1 mutation. The identification of PTCH1 mutations in previously mutation-negative families underscores the importance of repeated testing when new technologies become available. Additional clinical information linked to mutation databases would enhance follow-up and future studies of genotype-phenotype relationships.

Germline and somatic genetics of osteosarcoma - connecting aetiology, biology and therapy.

Clinical outcomes and treatment modalities for osteosarcoma, the most common primary cancer of bone, have changed very little over the past 30 years. The peak incidence of osteosarcoma occurs during the adolescent growth spurt, which suggests that bone growth and pubertal hormones are important in the aetiology of the disease. Tall stature, high birth weight and certain inherited cancer predisposition syndromes are well-described risk factors for osteosarcoma. Common genetic variants are also associated with osteosarcoma. The somatic genome of osteosarcoma is highly aneuploid, exhibits extensive intratumoural heterogeneity and has a higher mutation rate than most other paediatric cancers. Complex pathways related to bone growth and development and tumorigenesis are also important in osteosarcoma biology. In this Review, we discuss the contributions of germline and somatic genetics, tumour biology and animal models in improving our understanding of osteosarcoma aetiology, and their potential to identify novel therapeutic targets and thus improve the lives of patients with osteosarcoma.