Assessing a single SNP located at TERT/CLPTM1L multi-cancer risk region as a genetic modifier for risk of pancreatic cancer and melanoma in Dutch CDKN2A mutation carriers.

Carriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of CDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC in p16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients' surveillance. In a recent genome-wide association study (GWAS), rs36115365-C was found to significantly modify risk of PC and melanoma in the European population. This SNP is located on chr5p15.33 and has allele-specific regulatory activities on TERT expression. Herein, we investigated the modifying capacities of rs36115365-C on PC and melanoma in a cohort of 283 p16-Leiden carriers including 29 diagnosed with PC, 171 diagnosed with melanoma, 21 diagnosed with both PC and melanoma and 62 with neither PC nor melanoma. In contrast to previously reported findings, we did not find a significant association of PC risk with risk variant presence as determined by Generalized Estimating Equations (GEE) modelling. Interestingly, carrier-ship of the risk variant had a significant protective effect for melanoma (OR - 0.703 [95% CI - 1.201 to - 0.205], p = 0.006); however, the observed association was no longer significant after exclusion of probands to assess possible influence of ascertainment. Collectively, genetic modifiers for the prediction of PC and melanoma risk in p16-Leiden carriers remain to be determined.

Performance of BRCA1/2 mutation prediction models in male breast cancer patients.

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources.

A short-form version of the Boston Naming Test for language screening in dementia in a bilingual rural community in Galicia (Spain).

BACKGROUND: Aphasia, one of the core symptoms of cortical dementia, is routinely evaluated using graded naming tests like the Boston Naming Test (BNT). However, the application of this 60-item test is time-consuming and shortened versions have been devised for screening. The hypothesis of this research is that a specifically designed shortened version of the BNT could replace the original 60-item BNT as part of a mini-battery for screening for dementia. The objective of this study was to design a short version of the BNT for a rural population in Galicia (Spain). METHODS: A clinic group of 102 patients including 43 with dementia was recruited along with 78 healthy volunteers. The clinic and control groups were scored on the Spanish version of the Mini-mental State Examination (MMSE) and BNT. In addition, the clinic group was tested with standard neuropsychological instruments and underwent brain investigations and routine neurological examination. BNT items with specificity and sensitivity above 0.5 were selected to compose a short battery of 11 pictures named BNTOu11. ANOVA and mean comparisons were made for MMSE and BNT versions. Receiver operating characteristics (ROC) curves and internal consistency were calculated. RESULTS: Areas under ROC curves (AUC) did not show statistically significant differences; therefore BNTOu11's AUC (0.814) was similar to the 60-item BNT versions (0.785 and 0.779), to the short versions from Argentina (0.772) and Andalusia (0.799) and to the Spanish MMSE (0.866). BNTOu11 had higher internal consistency than the other short versions. CONCLUSIONS: BNTOu11 is a useful and time-saving method as part of a battery for screening for dementia in a psychogeriatric outpatient unit.