Insights into Land Plant Evolution Garnered from the Marchantia polymorpha Genome.

The evolution of land flora transformed the terrestrial environment. Land plants evolved from an ancestral charophycean alga from which they inherited developmental, biochemical, and cell biological attributes. Additional biochemical and physiological adaptations to land, and a life cycle with an alternation between multicellular haploid and diploid generations that facilitated efficient dispersal of desiccation tolerant spores, evolved in the ancestral land plant. We analyzed the genome of the liverwort Marchantia polymorpha, a member of a basal land plant lineage. Relative to charophycean algae, land plant genomes are characterized by genes encoding novel biochemical pathways, new phytohormone signaling pathways (notably auxin), expanded repertoires of signaling pathways, and increased diversity in some transcription factor families. Compared with other sequenced land plants, M. polymorpha exhibits low genetic redundancy in most regulatory pathways, with this portion of its genome resembling that predicted for the ancestral land plant. PAPERCLIP

Integrative Annotation of 21,037 Human Genes Validated by Full-Length cDNA Clones

The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology

Integrative annotation of 21,037 human genes validated by full-length cDNA clones.

publication en ligne. Article dans revue scientifique avec comité de lecture. nationale.National audienceThe human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology

Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab, trastuzumab, and docetaxel for advanced HER2-positive breast cancer

Abstract Background The trastuzumab, pertuzumab, and docetaxel (TPD) regimen is strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER) 2-positive breast cancer. Monitoring the host microenvironments in cancer plays a significant role in predicting prognoses and curative effects. It is important to clarify the role of immune related gene expression in tumor-infiltrating lymphocytes in the tumor microenvironment. In this study, we evaluated the impact of chemotherapy with a TPD regimen, on immune micro environments in HER2-positive breast cancer using immune related proteins as indicators. Methods The subjects consisted of 30 patients who received the TPD regimen. The expression levels of estrogen receptor, progesterone receptor, Ki67, CD8, forkhead box protein (FOXP) 3, programmed death (PD) 1, programmed death ligand (PD-L) 1, CD163, phosphatase and tensin homolog and lymphocyte activation gene 3 were evaluated in biopsy specimens, by immunostaining. Results CD8+, CD8/FOXP3 ratio (CFR)high and PD-L1− group had significantly longer PFS than the CD8−, CFRlow and PDL1+ group (p = 0.045, log-rank) (p = 0.007, log-rank) (p = 0.040, log-rank), respectively. The CFRhigh group had significantly better OS than the CFRlow group (p = 0.034, log-rank). In the univariate analysis, CD8+, CFRhigh groups extended PFS significantly (p = 0.027, hazard ratio [HR] = 0.162) (p = 0.008, HR = 0.195), respectively. The receiver operating characteristic (ROC) analyses showed that the results for CFR [area under the curve (AUC): 0.708] were better than those for other factors (AUC: CD8 = 0.681, FOXP3 = 0.639, PD1 = 0.528, PD-L1 = 0.681). Conclusions This study shows with the TPD regimen, a high CFR leads to a high ORR and long PFS in HER2-positive breast cancer. CFR, therefore, may be one of the important prognostic factors for this disease

Clinical verification of the relationship between smoking and the immune microenvironment of breast cancer

Abstract Background The immune tumor microenvironment (iTME) is thought to affect the response to chemotherapy, and tumor-infiltrating lymphocytes (TILs) are often used as an indicator to evaluate the iTME. Smoking is involved in carcinogenesis, the relationship between smoking and the iTME of lung cancer has been reported. We hypothesized that smoking would affect the iTME of breast cancer and aimed to examine this relationship based on the amount of pre-diagnosis smoking and the subsequent effects on treatment response and prognosis. Methods This retrospective study evaluated data from 149 patients who underwent preoperative chemotherapy for triple-negative or HER2-enriched breast cancer. TILs were assessed in biopsy specimens at diagnosis. The data of all patients were used to calculate each patient’s smoking amount based on pack-years. Results Relative to the low smoking group, the high smoking group had a significant greater TILs density (p = 0.043) and a significantly better pathological complete response (pCR) rate (p = 0.042). However, there was no significant difference according to smoking amount in disease-free survival (p = 0.114) or overall survival (p = 0.347). Conclusions Smoking may influence the iTME, with an activated iTME being associated with pCR rate. Therefore, controlled activation of the microenvironment in this setting may help improve patients’ prognosis

Possibility of avoiding axillary lymph node dissection by immune microenvironment monitoring in preoperative chemotherapy for breast cancer

Abstract Background The diagnosis of metastasis by sentinel lymph node biopsy (SLNB) in early breast cancer surgery provides an accurate view of the state of metastases to the axillary lymph nodes, and it has now become the standard procedure. In the present study, whether omission of axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC) is possible by evaluation of tumor-infiltrating lymphocytes (TILs) before NAC in cases without metastasis on diagnostic imaging, but with metastasis on SLNB, was retrospectively investigated. Methods A total of 91 patients with resectable, early-stage breast cancer, diagnosed as cT1–2, N0, M0, underwent SLNB and were treated with NAC. A semi-quantitative evaluation of lymphocytes infiltrating the peritumoral stroma as TILs in biopsy specimens of primary tumors prior to treatment was conducted. Results In cases with a low number of TILs, estrogen receptor expression was significantly higher (p = 0.044), and human epidermal growth factor receptor 2 (HER2) expression was significantly lower than in other cases (p = 0.019). The number of TILs was significantly lower in cases in which the intrinsic subtype was hormone receptor-positive breast cancer (HRBC) (p = 0.044). Metastasis to axillary lymph nodes was significantly more common in HER2-negative cases and cases with a low number of TILs (p = 0.019, p = 0.005, respectively). Conclusions Even if macrometastases are found on SLNB in cN0 patients, it appears that ALND could be avoided after NAC in cases with a good immune tumor microenvironment of the primary tumor

Significance of intrinsic breast cancer subtypes on the long-term prognosis after neoadjuvant chemotherapy

Abstract Background The prognosis of breast cancer and the treatment response to neoadjuvant chemotherapy (NAC) differ depending on the intrinsic molecular subtypes. We evaluated the prognostic significance of immunohistological subtypes in patients with recurrent breast cancer after treatment with NAC and surgery. Methods A total of 237 patients with breast cancer treated with NAC and subsequent curative surgery between 2007 and 2015 were analyzed. The correlation between intrinsic molecular subtypes and clinicopathological features, prognosis, and pathological complete response (pCR) rate of NAC were investigated retrospectively. Results There were 55 (23.2%) patients with recurrence after surgery. No significant difference in post-recurrence survival (PRS) was noted among the subtypes (p = 0.397). In patients with estrogen receptor-positive human epidermal growth factor receptor (HER) 2-negative (luminal) malignancy, PRS was significantly better in the pCR group than in the non-pCR group (p = 0.031). Conversely, pCR was not a significant predictor of improved PRS in patients with triple-negative breast cancer (TNBC; p = 0.329). Multivariate analysis revealed that the efficacy of NAC [hazard ratio (HR) 300.204, p < 0.001] and the initial metastasis site (HR 15.037, p = 0.005) were independent predictors for PRS in patients with luminal breast cancer, while Ki-67 (HR 51.171, p = 0.020) and the initial metastasis site (HR 13.318, p = 0.048) were independent predictors for PRS in patients with TNBC. Conclusions The prognostic factors for each intrinsic subtype should be evaluated separately in patients with recurrent breast cancer following NAC and surgery