No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 16 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defense (W81XWH-10-1- 0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Project established by the National Cancer Institute and National Human Genome Research Institute.This is the author accepted manuscript. The final version is available from BMJ Group at http://dx.doi.org/10.1136/jmedgenet-2015-103529

Weight loss and body mass index in relation to aspiration in patients treated for head and neck cancer: a long-term follow-up

Persistent severe swallowing dysfunction with aspiration is a common and sometimes overlooked sequelae after treatment for squamous cell carcinoma of the head and neck (SCCHN) and may impact food intake and nutritional status. More knowledge is needed to increase the understanding of severe swallowing dysfunction as a risk factor for persistent nutritional deteriorations in SCCHN survivors. The purpose of the study was to investigate weight loss and body mass index (BMI) in relation to pharyngeal swallowing function in a long-term perspective in patients after SCCHN treatment. Data from 101 patients were available for the analyses. Swallowing function was assessed by videofluoroscopy at a mean of 71.6 months after the start of radiotherapy (RT). Percent weight change (calculated with weight at the start of RT as the reference) and BMI at follow-up were the primary nutritional measures. Aspiration was present in 48 of 101 patients (48 %). Patients with aspiration had a significantly higher mean weight loss and a lower BMI (-10.9 % and 23.1, respectively) at follow-up compared with patients without aspiration (-2.8 % and 26.0, respectively). Patients with aspiration were unable to gain weight after 23 months. Only ten of 101 patients (10 %) were underweight at follow-up. Swallowing dysfunction with aspiration was related to long-term weight loss and reduced BMI. Few patients were underweight despite the high prevalence of swallowing dysfunction

The effects of syllable boundary, stop consonant closure duration, and VOT on VCV coarticulation

This study investigated whether the vocalic gestures in VCV sequences are produced with a single diphthongal movement as predicted by the superimposition model of coarticulation or as separate events as predicted by a phoneme-by-phoneme view. ‘Troughs’ or discontinuities in anticipatory vowel-to-vowel coarticulation during the closure period of bilabial stops in symmetrical VCV sequences have provided evidence in favor of a phoneme-by-phoneme view. This investigation sought to uncover the acoustic correlates of troughs in VCV utterances produced by five English and two Persian speakers. Acoustic evidence for troughs was found in frequency changes of F2 transitions in symmetrical [V.bV] and [V.phV] sequences. F2 transitions indicative of tongue-related trough effects were influenced by the syllabic affiliation of the intervocalic stop and to a lesser degree by its voicing properties. Changes in consonantal closure duration did not elicit troughs. Locus equations (LE) were employed as a second methodology to uncover the acoustic correlates of troughs in a variety of consonantal and vocalic contexts. LE slopes capture CV coarticulation. Troughs would be expected to lower slope values. Consistently lower LE slopes at the CV2 interface were observed with closed versus open and voiceless versus voiced stops. LE slopes remained stable across changes in consonantal closure duration. Bidirectional V-to-V coarticulatory effects were also explored. The superimposition model predicts no changes in V-to-V coarticulation as a function of the syllabic affiliation, closure duration, and the voicing properties of an intervocalic stop. Results showed reduced anticipatory V-to-V effects in closed versus open, geminate versus singleton, and voiceless versus voiced conditions in English and with lesser degrees of consistency in Persian. Increased carry-over V-to-V effects were observed in closed versus open syllables in English and in voiceless versus voiced conditions in Persian. Carry-over effects were generally smaller in geminate versus singleton utterances in English and Persian and across voiceless versus voiced stops in English. The results of this study support a phoneme-by-phoneme view of segmental organization in which vocalic and consonantal gestures are distinct, but temporally and spatially overlapping events and affect one another in varying degrees based on the degree of their overlap.Linguistic

On the pragmatics of subjectification: The grammaticalization of verbless allative futures (with a case study in Ancient Egyptian)

peer reviewedIn this paper, we argue that an expanded conception of the distinction between speaker-oriented and subject-oriented inferences is crucial for understanding the motivations and mechanisms of semantic change in grammaticalization and subjectification, on the one hand, and for clarifying the links between semantic change and reductive formal changes, on the other. Speaker-oriented inferences have significant consequences, leading to the relaxation of selectional restrictions on a construction. In turn, the relaxation of selectional restrictions can create conditions in which the type and token frequency of a construction can rise considerably. Furthermore, changes in the selectional restrictions on a construction can themselves catalyze semantic change by coercing listeners into new form–function pairings. This framework is applied to allative futures, a typological comparative concept developed in order to compare structurally diverse future tenses. Following the typological discussion, a diachronic case study of the emergence and grammaticalization of a verbless allative future in Ancient Egyptian is presented. Such verbless allative futures provide evidence against assumptions that purpose constructions as such are not grammaticalized as future tense constructions (Schmidtke-Bode 2009). Rather, they corroborate earlier hypotheses that it is the allative component of source constructions that crucially leads to intention meanings, and from intention to prediction (see, e.g., Bybee, Pagliuca, and Perkins 1994)