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The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Peutz–Jeghers syndrome (PJS) is an autosomal dominant hereditary polyposis syndrome causing increased morbidity and mortality due to complications of polyposis and the development of cancer. STK11 is the only gene known to be associated with PJS, although in 10%–15% of patients fulfilling the diagnostic criteria no pathogenic variant (PV) is identified. The primary aim of this study was to identify the genetic etiology in all known PJS patients in Denmark and to estimate the risk of cancer, effect of surveillance and overall survival. We identified 56 patients (2–83 years old) with PJS. The detection rate of PVs was 96%, including three cases of mosaicism (6%). In two patients a variant was not detected. At the age of 40 years, the probabilities of cancer and death were 21% and 16%, respectively; at the age of 70 years these probabilities were 71% and 69%. Most cases of cancer (92%) were identified between the scheduled examinations in the surveillance program. These observations emphasize that PJS should be regarded as a general cancer predisposition syndrome, where improvement of clinical care is needed. [ABSTRACT FROM AUTHOR]

Background: Every year more than 800 patients in Denmark are diagnosed with renal cell carcinoma (RCC) of which 3–5% are expected to be part of a hereditary renal cancer syndrome. We performed genetic screening of causative and putative RCC-genes (VHL, FH, FLCN, MET, SDHB, BAP1, MITF, CDKN2B) in RCC-patients suspected of a genetic predisposition. Methods: The cohort consisted of forty-eight Danish families or individuals with early onset RCC, a family history of RCC, a family history of RCC and melanoma or both RCC- and melanoma diagnosis in the same individual. DNA was extracted from peripheral blood samples or cancer-free formalin-fixed paraffin-embedded tissue. Results: One start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von Hippel-Lindau (VHL). Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC. Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas. No variants were detected in CDKN2B. Conclusion: Although we did find three VUS’s in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark. It is possible that the high prevalence of risk factors such as male gender, smoking and obesity has influenced the development of cancer in the patients of the current study. Further investigations into putative predisposing genes and risk factors of RCC are necessary to enable better prediction of renal cancer risk or presymptomatic testing of relatives in hereditary renal cancer families. [ABSTRACT FROM AUTHOR]

The development of hip dysplasia is associated with several risk factors. 1 of these risk factors is gender, since 80% of patients with symptomatic hip dysplasia are females. Another risk factor for hip dysplasia is familial predisposition of hip dysplasia. Several studies indicate that the risk of hip dysplasia is increased with familial prevalence of hip dysplasia. However, little is known about the association between the familial prevalence and gender and the development of hip dysplasia.~Background~Background~The aim of the study was to estimate the prevalence of hip dysplasia among relatives to Danish patients with hip dysplasia operated with periacetabular osteotomy (PAO), and the degree of relationship of affected family members. Furthermore, to assess the association between gender and family predisposition in the same group of patients.~Purpose~Objective~The study is a cross-sectional study, with a descriptive and an analytical part. The study population consists of 676 patients drawn from a clinical database of patients operated with PAO at Aarhus University hospital from 1998 to 2014. Information about gender, operated hip side and age was collected from the clinical PAO database, while information about familial prevalence was collected through questionnaires. The association between gender and familial prevalence of hip dysplasia was presented as the prevalence proportions ratio (PPR), tested by ¿2 test. Stratification was conducted for the variables age and operated hip side, with the Mantel-Haenszels analytical method, and tested for statistical significance by ¿2.~Method~Methods~The familial prevalence of hip dysplasia in the study population was 30% (95% CI, 27%-34%), with 73% reporting affected first-degree relatives. Females have 32% increased risk of familial prevalence of hip dysplasia compared to males, but this difference in risk was not statistically significant (p = 0.10).~Results~Results~The study shows that females have 32% increased familial prevalence of hip dysplasia compared to males, but the increased prevalence was not statistically significant probably due to the low power of the study.~Conclusions~Conclusions [ABSTRACT FROM AUTHOR]