Prediction of breast cancer risk based on profiling with common genetic variants

BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.

Convergence in word structure: revisiting agglutinative noun inflection in Cappadocian Greek

Cappadocian Greek is reported to display agglutinative inflection in its nominal system, namely, mono-exponential formatives for the marking of case and number, and NOM.SG-looking forms as the morphemic units to which inflection applies. Previous scholarship has interpreted these developments as indicating a shift in morphological type from fusion to agglutination, brought about by contact with Turkish. This study takes issue with these conclusions. By casting a wider net over the inflectional system of the language, it shows that, of the two types of agglutinative formations identified, only one evidences a radical departure from the inherited structural properties of Cappadocian noun inflection. The other, on the contrary, represents a typologically more conservative innovation. The study presents evidence that a combination of system-internal and -external motivations triggered the development of both types, it describes the mechanisms through which the innovation was implemented, and discusses the factors that favoured change.