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Fusarium head blight, mainly incited by Fusarium graminearum, is a devastating wheat disease worldwide. Diverse Fusarium head blight (FHB) resistant sources have been reported, but the resistance mechanisms of these sources remain to be investigated. FHB-resistant wheat germplasm often shows black necrotic lesions (BNLs) around the infection sites. To determine the relationship between BNL and FHB resistance, leaf tissue of a resistant wheat cultivar Sumai 3 was inoculated with four different F. graminearum isolates. Integrated metabolomic and transcriptomic analyses of the inoculated samples suggested that the phytohormone signaling, phenolamine, and flavonoid metabolic pathways played important roles in BNL formation that restricted F. graminearum extension. Exogenous application of flavonoid metabolites on wheat detached leaves revealed the possible contribution of flavonoids to BNL formation. Exogenous treatment of either salicylic acid (SA) or methyl jasmonate (MeJA) on wheat spikes significantly reduced the FHB severity. However, exogenous MeJA treatment prevented the BNL formation on the detached leaves of FHB-resistant wheat Sumai 3. SA signaling pathway influenced reactive oxygen species (ROS) burst to enhance BNL formation to reduce FHB severity. Three key genes in SA biosynthesis and signal transduction pathway, TaICS1, TaNPR1, and TaNPR3, positively regulated FHB resistance in wheat. A complex temporal interaction that contributed to wheat FHB resistance was detected between the SA and JA signaling pathways. Knowledge of BNLs extends our understanding of the molecular mechanisms of FHB resistance in wheat and will benefit the genetic improvement of wheat FHB resistance.

Early identification of the risk for triple-negative breast cancer (TNBC) at the asymptomatic phase could lead to better prognosis. Here we developed a machine learning method to quantify systematic impact of all rare germline mutations on each pathway. We collected 106 TNBC patients and 287 elder healthy women controls. The spectra of activity profiles in multiple pathways were mapped and most pathway activities exhibited globally suppressed by the portfolio of individual germline mutations in TNBC patients. Accordingly, all individuals were delineated into two types: A and B. Type A patients could be differentiated from controls (AUC = 0.89) and sensitive to BRCA1/2 damages; Type B patients can be also differentiated from controls (AUC = 0.69) but probably being protected from BRCA1/2 damages. Further we found that Individuals with the lowest activity of selected pathways had extreme high relative risk (up to 21.67 in type A) and increased lymph node metastasis in these patients. Our study showed that genomic DNA contains information of unimaginable pathogenic factors. And this information is in a distributed form that could be applied to risk assessment for more cancer types.Significance: We identified individuals who are more susceptible to triple negative breast cancer. Our method performs much better than previous assessments based on BRCA1/2 damages, even polygenic risk scores. We disclosed previously unimaginable pathogens in a distributed form on genome and extended risk prediction to scenarios for other cancers.

BackgroundBreast cancers can be divided into HER2-negative and HER2-positive subtypes according to the status of HER2 gene. Despite extensive studies connecting germline mutations with possible risk of HER2-negative breast cancer, the main category of breast cancer, it remains challenging to accurately assess its potential risk and to understand the potential mechanisms.MethodsWe developed a novel framework named Damage Assessment of Genomic Mutations (DAGM), which projects rare coding mutations and gene expressions into Activity Profiles of Signalling Pathways (APSPs).FindingsWe characterized and validated DAGM framework at multiple levels. Based on an input of germline rare coding mutations, we obtained the corresponding APSP spectrum to calculate the APSP risk score, which was capable of distinguish HER2-negative from HER2-positive cases. These findings were validated using breast cancer data from TCGA (AUC = 0.7). DAGM revealed the HER2 signalling pathway was up-regulated in the germline of HER2-negative patients, and those with high APSP risk scores had suppressed immunity. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk of developing HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations.InterpretationThe DAGM can facilitate the screening of subjects at high risk of HER2-negative breast cancer for primary prevention. This study also provides new insights into the potential mechanisms of developing HER2-negative breast cancer. The DAGM has the potential to be applied in the prevention, diagnosis, and treatment of HER2-negative breast cancer.FundingThis work was supported by the National Key Research and Development Program of China (grant no. 2018YFC0910406 and 2018AAA0103302 to CZ); the National Natural Science Foundation of China (grant no. 81202076 and 82072939 to MY, 81871513 to KW); the Guangzhou Science and Technology Program key projects (grant no. 2014J2200007 to MY, 202002030236 to KW); the National Key R&D Program of China (grant no. 2017YFC1309100 to CL); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW)Research in contextEvidence before this studyThe majority of hereditary breast cancers are caused by BRCA1/2 mutations, and the presence of these mutations is strongly associated with an increased risk of breast cancer. Meanwhile, BRCA1/2 gene mutations are rarely found in sporadic breast cancers and only account for a modest percentage of all breast cancer patients. Polygenic risk score (PRS), a widely-used approach for stratifying individuals according to their risk of a certain kind of complex disease, has been used to predict subjects at high risk for breast cancer. However, relying on SNPs from genome-wide association studies (GWAS) without including gene expressions or pathway activities, PRS is not very suitable for cross-population prediction and describes disease risk in terms of genomic mutations without alluding to the underlying pathogenic mechanism(s). Therefore, there is still an urgent need for a population-independent comprehensive method to accurately assess the risk of breast cancer and to gain insights on potential mechanism(s).Added value of this studyWhen subjecting germline rare coding mutations (gRCMs) to DAGM framework, which results in the corresponding APSP and APSP risk score. Both APSP and APSP risk score can identify HER2-negative from HER2-positive breast cancers. These findings suggest HER2-negative breast cancer does not develop accidentally, but rather is defined by a genomic evolutionary strategy. Furthermore, this study also revealed the up-regulation of HER2 signalling pathway in germlines of HER2-negative breast cancers and the immune suppression in subjects with high APSP risk score, shedding new light on the potential mechanisms of developing HER2-negative breast cancer. Moreover, our APSP risk score was able to relatively accurately evaluate the risk of developing HER2-negative breast cancer for each female, including not only BRCA1/2 carriers, but also non-carriers.Implications of all the available evidenceThe present study suggests that HER2 signalling pathway activity, as an aggressive factor, contribute to the development of different types of breast cancers, either via the combined effects of multiple germline mutations in HER2-negative germlines or via amplifying the gene itself in HER2-positive tumour cells. This provides a theoretical basis for the prevention, diagnosis, and treatment of breast cancers. At the same time, the study provides preliminary methods for assessing the relative risk of HER2-negative breast cancer for females with or without BRCA1/2 mutations. Finally, our findings provide a new perspective and theoretical basis for identifying high-risk female subjects, based on the high APSP risk score, for early screening and prevention of HER2-negative breast cancer.