Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.

PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Inner border--a specific and significant colposcopic sign for moderate or severe dysplasia (cervical intraepithelial neoplasia 2 or 3).

OBJECTIVE: Investigation of the correlation between the colposcopic sign inner border and cervical intraepithelial neoplasia (CIN) 2 or 3 and its association with specific human papillomavirus (HPV) types and the age of the patient. STUDY DESIGN: Colpophotographs or cervicograms were taken from 947 women referred due to an abnormal cervical finding. Occurrence of the colposcopic sign inner border was evaluated retrospectively by 2 independent colposcopists. Histologic evaluation was based on punch or cone biopsies. Human papillomavirus testing was done using Hybrid Capture I or a polymerase chain reaction-based HPV test. RESULTS: The prevalence of the colposcopic phenomenon inner border in women with an atypical transformation zone was 7.6% (53/695). In 70% of women with inner border, CIN 2 or 3 was confirmed histologically. The sensitivity of the colposcopic sign inner border for detection of CIN 2 or 3 was 20%, and the specificity was 97%. In patients with inner border, the odds ratio for CIN 2 or 3 was 7.7 (95% CI=4.2-14.3). There was no significant association between inner border and any high-risk HPV type. Cervical intraepithelial neoplasia 2 or 3 associated with inner border was significantly more frequent in patients younger than 35 years. CONCLUSION: Inner border is a rare colposcopic phenomenon but highly specific for CIN 2 or 3 in young women.

The colposcopic feature ridge sign is associated with the presence of cervical intraepithelial neoplasia 2/3 and human papillomavirus 16 in young women.

OBJECTIVE: Interobserver and intraobserver correlation between the colposcopic phenomenon ridge sign and its association with cervical intraepithelial neoplasia (CIN) 2 or 3, with a specific human papillomavirus (HPV) type, and with the age of the patient. STUDY DESIGN: Colpophotographs, cervical smears, and histologic results of punch or cone biopsies of 592 patients were evaluated. Colpophotographs were analyzed retrospectively for the presence or absence of an opaque acetowhite ridge at the squamocolumnar junction (ridge sign) by 3 gynecologists of different experience. RESULTS: Interobserver reliability for colposcopic grading of CIN was between 18.2% and 82.3%. Concerning the ridge sign, interobserver agreement varied between 25.3% and 49.4% according to the observers' experience, and intraobserver reliability varied between 56.4% and 67.5% (Cohen kappa=0.310-0.469). In 83 (14.0%) of 592 patients, a ridge sign was diagnosed by the most experienced investigator. Cervical intraepithelial neoplasia 2 or 3 was confirmed histologically in 53 of these 83 women (63.8%). Sensitivity of ridge sign for detection of CIN 2 or 3 was 33.1%; specificity was 93.1%. Women with ridge sign were significantly younger than women with no ridge sign (p< .001). Ridge sign was associated with the presence of HPV 16 (p< .001). CONCLUSION: Ridge sign is a highly specific marker for CIN 2 or 3 and associated with HPV 16 and young age.