The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM (-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

RF Small-Signal and Noise Modeling Including Parameter Extraction of Nanoscale MOSFET From Weak to Strong Inversion

The downscaling of CMOS processes has led to devices with an impressive RF performance. Advanced nanoscale RF MOSFETs present very high transit frequency, which can be traded off with lower power consumption, by shifting the operating point towards the weak inversion (WI) regime. This paper explores whether the simple RF schematics and models used in strong inversion remain valid in moderate or even down to deep WI regions for nanoscale devices. A simple RF equivalent circuit is proposed, leading to first-order analytical expressions, which are able to describe the RF small-signal behavior of nanoscale MOSFET, including noise, across all inversion levels. Using these expressions it is possible to extract the values of all the RF components and noise model parameters directly from measurements. The analytical models are compared to RF measurements of a commercial state-of-the-art 40-nm CMOS process and to the advanced BSIM6 compact bulk MOSFET model, showing very good accuracy

Charge-Based Distortion Analysis of Nanoscale MOSFETs

This paper presents a study of MOSFETs' linearity, exploiting a simplified version of the charge-based EKV model. It allows to deduce analytically the one-tone and two-tone harmonic distortions introduced by the nonlinear ID-VG MOSFET characteristic as a function of the inversion coefficient. The short-channel effects are included in order to address nanoscale MOSFET performance. The analysis is validated through comparisons with the BSIM6 model and measurement results from 28-nm bulk CMOS devices. By means of this model, the designer can choose the appropriate bias region for the critical devices of a circuit depending on the system requirements