Mitochondrial D310 mutation as clonal marker for solid tumors

Patients with multiple tumors, either synchronous or metachronous, can have metastatic disease or suffer from multiple independent primary tumors. While proper diagnosis of these patients is important for prognosis and treatment, this can be challenging using only clinical and histological criteria. The aim of the present study was to evaluate the value of mitochondrial D310 mutation analysis in diagnostic questions regarding tumor clonality for a wide range of tumor types. Sanger sequencing of D310 was performed on a diagnostic cohort of 382 patients with 857 tumors that were previously analyzed using routine molecular analysis on genomic DNA. The D310 mononucleotide repea

HPV Prevalence in the Dutch cervical cancer screening population (DuSC study): HPV testing using automated HC2, cobas and Aptima workflows

Background: Primary high risk (hr)HPV screening will be introduced in The Netherlands in January 2017. Our aim was to determine the hrHPV prevalence in the Dutch cervical cancer screening population (DuSC study). Methods: A total of 12,113 residual PreservCyt cervical samples from the Dutch population based cytology screening program were rendered anonymous, randomized and tested for hrHPV using 3 HPV assays on their respective automated platforms: QIAGEN's digene® HC2 HPV DNA Test® (HC2, signal amplification), Roche Cobas® HPV test (DNA amplification) and Hologic Aptima® HPV Test (RNA amplification). To determine the agreement between results generated using the different assays, pair wise comparison of the systems was performed by determining kappa coefficients. Results: The selected samples were representative for the population based screening program with respect to age distribution and cytology classification. HrHPV prevalences found were: 8.5% for HC2 (n = 959), 8.1% for cobas (n = 919) and 7.5% for Aptima (n = 849), resulting in a mean hrHPV prevalence of 8.0 ± 0.5%. Although the hrHPV prevalences of the different assays are in the range of 8%, there was a significant difference in prevalence for the HC2 vs. Aptima assay (p-value = 0.007). A clear age dependency was found, with an hrHPV prevalence ranging from 18.7 ± 1.2% in women 29-33 years of age to 4.2 ± 0.2% in women 59-63 years of age. Furthermore, a correlation between hrHPV prevalence and severity of cytology was observed, ranging from 5.5 ± 0.4% in normal cytology to 95.2 ± 1.7% in severe dysplasia. Indeed, kappa coefficients of 0.77, 0.71 and 0.72 (HC2 vs cobas, cobas vs Aptima and Aptima vs HC2, respectively) indicated substantial agreement between the results generated by the different systems. However, looking at the hrHPV positive samples, only 48% of the samples tested positive with all 3 assays. Conclusions: A hrHPV prevalence of 8% was found in this unselected population based screening cohort independently of using HC2, Aptima or cobas. This prevalence is higher than the previously reported 4-5% (POBASCAM and VUSA-Screen trials). Furthermore, the complete automated hrHPV detection workflow solutions from QIAGEN, Roche, and Hologic were successfully used and will be valuable for reliably implementing high throughput hrHPV testing in cervical cancer screening

Gynecological surveillance and surgery outcomes in dutch lynch syndrome carriers

Female Lynch syndrome (LS) carriers have an increased risk to develop endometrial and ovarian cancer. In the Netherlands, carriers are therefore advised annual gynecological surveillance and eventually, risk-reducing surgery. Global gynecological LS surveillance guidelines are scarce and based on limited evidence. These are, however, warranted to offer accurate surveillance. To provide more insight into surveillance outcomes, this study assessed outcomes of gynecological surveillance and risk-reducing surgery in 164 LS carriers diagnosed in our center, with a median follow-up of 5.6 years per carrier. Although most surveillance visits happened within an advised timeframe, we observed large variability in how gynecological surveillance visits were performed. This finding stresses the need for development of clear and evidence-based guidelines. Endometrial cancers identified at surveillance were all found in early stage, mostly symptomatic, questioning surveillance benefit. Large, prospective studies should assess to what extent current LS surveillance programs contribute to early detection of gynecological tumors. Lynch syndrome (LS) is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, predisposing female carriers for endometrial cancer (EC) and ovarian cancer (OC). Since gynecological LS surveillance guidelines are based on little evidence, we assessed its outcomes. Data regarding gynecological tumors, surveillance, and (risk-reducing) surgery were collected from female LS carriers diagnosed in our center since 1993. Of 505 female carriers, 104 had a gynecological malignancy prior to genetic LS diagnosis. Of 264 carriers eligible for gynecological management, 164 carriers gave informed consent and had available surveillance data: 38 MLH1, 25 MSH2, 82 MSH6, and 19 PMS2 carriers (median follow-up 5.6 years). Surveillance intervals were within advised time in >80%. Transvaginal ultrasound, endometrial sampling, and CA125 measurements were performed in 76.8%, 35.9%, and 40.6%, respectively. Four symptomatic ECs, one symptomatic OC, and one asymptomatic EC were diagnosed. Endometrial hyperplasia was found in eight carriers, of whomthree were symptomatic. Risk-reducing surgery was performed in 73 (45.5%) carriers (median age 51 years), revealing two asymptomatic ECs. All ECs were diagnosed in FIGO I. Gynecological management in LS carriers varied largely, stressing the need for uniform, evidence-based guidelines. Most ECs presented early and symptomatically, questioning the surveillance benefit in its current form