Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes.

BACKGROUND: Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical features. >70 IBMFS genes have been identified, which often renders genetic testing prolonged and costly. Since correct diagnosis, treatment and cancer surveillance often depend on identifying the mutated gene, strategies that enable timely genotyping are essential. METHODS: To overcome these challenges, we developed a next-generation sequencing assay to analyse a panel of 72 known IBMFS genes. Cases fulfilling the clinical diagnostic criteria of an IBMFS but without identified causal genotypes were included. RESULTS: The assay was validated by detecting 52 variants previously found by Sanger sequencing. A total of 158 patients with unknown mutations were studied. Of 75 patients with known IBMFS categories (eg, Fanconi anaemia), 59% had causal mutations. Among 83 patients with unclassified IBMFSs, we found causal mutations and established the diagnosis in 18% of the patients. The assay detected mutant genes that had not previously been reported to be associated with the patient phenotypes. In other cases, the assay led to amendments of diagnoses. In 20% of genotype cases, the results indicated a cancer surveillance programme. CONCLUSIONS: The novel assay is efficient, accurate and has a major impact on patient care.

Ovarian cancer familial relative risks by tumour subtypes and by known ovarian cancer genetic susceptibility variants.

BACKGROUND: Family history is one of the most important risk factors for epithelial ovarian cancer (EOC). Little is known, however, on how EOC familial relative risks (FRRs) vary by factors such as tumour subtype or the combined effects of common EOC susceptibility alleles. In addition, no data currently exist on the FRRs associated with EOC after exclusion of BRCA1 or BRCA2 mutation carriers. METHODS: EOC FRRs were computed from observed EOCs in relatives of 1548 patients with EOC recruited between 1999 and 2010 from a population-based cohort study with known BRCA1 and BRCA2 mutation status and tumour subtype, compared with the number expected in the general population. RESULTS: The EOC FRR to all first-degree relatives was estimated to be 2.96 (95% CI 2.35 to 3.72) but there was no evidence of difference in the FRRs for mothers, sisters and daughters. There was significant evidence that the FRR for relatives of patients with EOC diagnosed under age 50 years is higher than that for older patients (4.72 (95% CI 3.21 to 6.95) and 2.53 (95% CI 1.91 to 3.35), p-diff=0.0052) and a suggestion that the FRR in relatives of patients with serous disease is higher than that for non-serous tumours (3.64 (95% CI 2.72 to 4.87) and 2.25 (95% CI 1.56 to 3.26), p-diff=0.0023). The FRR to relatives of cases without a deleterious mutation in BRCA1 or BRCA2 was estimated to be over twice that of the general population (2.24 (95% CI 1.71 to 2.94)). BRCA1 and BRCA2 mutations were estimated to account for about 24% of the EOC FRR to first-degree relatives. FRRs were found to increase with increasing polygenic risk score of the index patient, although the trend was not significant. CONCLUSIONS: These estimates could be useful in the counselling of relatives of patients with ovarian cancer.

A critical appraisal of the quality of data submitted by sub-Saharan African cancer registries to GLOBOCAN 2020.

Objectives: (a) To critically appraise the quality of data submitted by sub-Saharan African (SSA) cancer registries to GLOBOCAN 2020 and (b) compare the quality of data of the registries common to GLOBOCAN 2008 and 2020. Design: Critical appraisal of cancer registry data quality using the Parkin and Bray framework. Setting and Participants: GLOBOCAN 2020 cancer registry estimates for 46 countries in SSA. Forty-three registries in 31 (SSA) countries were identified from the GLOBCAN 2020 supplementary documents, of which data from 28 registries in 23 sub-Saharan African countries were publicly available. Main outcomes measures: Data quality for 15 variables in four domains (comparability, validity, timeliness and completeness) were appraised using the Parkin and Bray framework. Results from the appraisal of GLOBOCAN 2020 sources were compared with previous findings for GLOBOCAN 2008. Results: Compared with GLOBOCAN 2008, GLOBOCAN 2020 country coverage had increased from 21 to 31 countries with 15 countries having no established registries. Out of a total possible score of 15 for data quality, 18 of the 28 publicly available GLOBOCAN 2020 registries fulfilled a score of 5 or more compared with seven registries in GLOBOCAN 2008. Of the 17 registries common to GLOBOCAN 2008 and 2020, nine showed an improvement in data quality. Conclusion: Country coverage and data quality have improved since GLOBOCAN 2008, however, overall data quality and coverage remain poor. GLOBOCAN 2020 estimates should be used with caution when allocating resources.