Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.
We present first evidence that the cosine of the CP-violating weak phase 2β is positive, and hence exclude trigonometric multifold solutions of the Cabibbo-Kobayashi-Maskawa (CKM) Unitarity Triangle using a time-dependent Dalitz plot analysis of B^{0}→D^{(*)}h^{0} with D→K_{S}^{0}π^{+}π^{-} decays, where h^{0}∈{π^{0},η,ω} denotes a light unflavored and neutral hadron. The measurement is performed combining the final data sets of the BABAR and Belle experiments collected at the ϒ(4S) resonance at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. The data samples contain (471±3)×10^{6}BB[over ¯] pairs recorded by the BABAR detector and (772±11)×10^{6}BB[over ¯] pairs recorded by the Belle detector. The results of the measurement are sin2β=0.80±0.14(stat)±0.06(syst)±0.03(model) and cos2β=0.91±0.22(stat)±0.09(syst)±0.07(model). The result for the direct measurement of the angle β of the CKM Unitarity Triangle is β=[22.5±4.4(stat)±1.2(syst)±0.6(model)]°. The measurement assumes no direct CP violation in B^{0}→D^{(*)}h^{0} decays. The quoted model uncertainties are due to the composition of the D^{0}→K_{S}^{0}π^{+}π^{-} decay amplitude model, which is newly established by performing a Dalitz plot amplitude analysis using a high-statistics e^{+}e^{-}→cc[over ¯] data sample. CP violation is observed in B^{0}→D^{(*)}h^{0} decays at the level of 5.1 standard deviations. The significance for cos2β>0 is 3.7 standard deviations. The trigonometric multifold solution π/2-β=(68.1±0.7)° is excluded at the level of 7.3 standard deviations. The measurement resolves an ambiguity in the determination of the apex of the CKM Unitarity Triangle.