Mutational signatures reveal mutual exclusivity of homologous recombination and mismatch repair deficiencies in colorectal and stomach tumors.

Decomposing somatic mutation spectra into mutational signatures and their corresponding etiologies provides a powerful approach for investigating the mechanism of DNA damage and repair. Assessing microsatellite (in)stability (MSI/MSS) status and interpreting their clinical relevance in different malignancies offers significant diagnostic and prognostic value. However, little is known about microsatellite (in)stability and its interactions with other DNA repair mechanisms such as homologous recombination (HR) in different cancer types. Based on whole-genome/exome mutational signature analysis, we showed HR deficiency (HRd) and mismatch repair deficiency (MMRd) occur in a significantly mutually exclusive manner in stomach and colorectal adenocarcinomas. ID11 signature with currently unknown etiology was prevalent in MSS tumors, co-occurred with HRd and was mutually exclusive with MMRd. Apolipoprotein B mRNA editing enzyme, Catalytic polypeptide-like (APOBEC) signature co-occurred with HRd and was mutually exclusive with MMRd in stomach tumors. The HRd signature in MSS tumors and the MMRd signature in MSI tumors were the first or second dominant signatures wherever detected. HRd may drive a distinct subgroup of MSS tumors and lead to poor clinical outcome. These analyses offer insight into mutational signatures in MSI and MMS tumors and reveal opportunities for improved clinical diagnosis and personalized treatment of MSS tumors.

Imprecision in vaccine adverse event reporting and a methodological analysis of reporting systems to improve pharmacovigilance and public health.

INTRODUCTION: This study documents imprecision in Japanese reports of adverse events following immunization (AEFI). In doing so, it presents methods to analyze this imprecision. METHODS: These methods include use of unique Japanese data on the validity of certain AEFIs. They also include ways to estimate AEFI rates, which allow comparison of AEFI data between countries. Using US AEFI data for comparison, we show how differences in AEFI reporting systems likely influence AEFI statistics. RESULTS: Although our comparisons of AEFI rates are not precise, many of the difference we detected between Japanese and US statistics make sense and reflect differences in the societal and medical perspectives on various vaccines or can be explained by differences in the reporting systems including reporting sources. For example, differences in societal and medical perspective probably underly the extraordinarily high Japanese rates of anaphylaxis and other AEs following HPV immunizations from 2010 to 2016 compared to US rates and to Japanese rates for other vaccines. High US rates of reported Guillain-Barré syndrome following influenza vaccination relative to Japanese rates and to rates for other US vaccines are consistent with data suggesting that the index of suspicion for such reactions could affect AEFI rates. The findings that over half of Japanese anaphylaxis reports for every vaccine are erroneous, and that close to half of "serious" Japanese AEFI cases probably are not serious may be due in part not only to explanations unique to Japan, but also to factors that apply to the USA and other countries. Differences in reporting systems account for a much higher rate of non-serious AEFI reports in the USA compared to Japan. Japanese marketing authorization holders are probably at least as assiduous and timely in their reporting of AEFIs as health care providers, though granular level differences are apparent in reporting by various sources. CONCLUSION: The methods we used to analyze the validity of Japanese statistics can be used to analyze the validity of AEFI reports from other countries and aid the harmonization of adverse event reporting systems. Eventually, similar reporting systems might be adapted for drugs and medical devices.

Imprecision in adverse event reports following immunization against HPV in Japan and COVID-19 in the USA, UK, and Japan-and the effects of vaccine hesitancy and government policy.

INTRODUCTION: Erroneous reports of adverse events following immunization (AEFIs) likely exacerbated the 2013 collapse of Japan's HPV immunization program. A similar phenomenon characterized the first months of COVID-19 immunization programs in the USA, UK, and Japan with high rates of reported anaphylaxis. These reports illustrate the susceptibility of supposedly objective medical judgments to public anxiety. PURPOSE AND METHODS: This study documents inaccuracies in reported AEFIs using three quantitative methods. RESULTS: One of these quantitative methods revealed that false-positive rates for anaphylaxis reports following HPV and later COVID-19 vaccination ranged from 74 to 91 percent. However, unlike HPV vaccinations in Japan, anaphylaxis reports following COVID-19 vaccines fell in Japan, the USA and the UK in the latter months of 2021. Nevertheless, false-positive rates for anaphylaxis reports remained high, suggesting a high degree of imprecision in serious AEFI reports from many countries for many vaccines. Japan's HPV immunization program indicates that media reports, patient hesitancy, healthcare providers' perspectives on vaccine safety, and consistency of government messaging, all influence report number and accuracy. A parallel publication analyzes in depth how such factors affect AEFI reports. CONCLUSION: Confidence in the safety of the COVID-19 vaccines may have been bolstered trough rapid monitoring of AEFI reports and communication of these findings. This may partly explain the different trajectories of serious AEFI following HPV immunizations in Japan and COVID-19 immunizations in the USA, UK, and Japan.

Mutational signatures reveal ternary relationships between homologous recombination repair, APOBEC, and mismatch repair in gynecological cancers.

BACKGROUND: Revealing the impacts of endogenous and exogenous mutagenesis processes is essential for understanding the etiology of somatic genomic alterations and designing precise prognostication and treatment strategies for cancer. DNA repair deficiency is one of the main sources of endogenous mutagenesis and is increasingly recognized as a target for cancer therapeutics. The role and prevalence of mechanisms that underly different forms of DNA repair deficiencies and their interactions remain to be elucidated in gynecological malignancies. METHODS: We analyzed 1231 exomes and 268 whole-genomes from three major gynecological malignancies including uterine corpus endometrial carcinoma (UCEC) as well as ovarian and cervical cancers. We also analyzed data from 134 related cell lines. We extracted and compared de novo and refitted mutational signature profiles using complementary and confirmatory approaches and performed interaction analysis to detect co-occurring and mutually exclusive signatures. RESULTS: We found an inverse relationship between homologous recombination deficiency (HRd) and mismatch repair deficiency (MMRd). Moreover, APOBEC co-occurred with HRd but was mutually exclusive with MMRd. UCEC tumors were dominated by MMRd, yet a subset of them manifested the HRd and APOBEC signatures. Conversely, ovarian tumors were dominated by HRd, while a subset represented MMRd and APOBEC. In contrast to both, cervical tumors were dominated by APOBEC with a small subsets showing the POLE, HRd, and MMRd signatures. Although the type, prevalence, and heterogeneity of mutational signatures varied across the tumor types, the patterns of co-occurrence and exclusivity were consistently observed in all. Notably, mutational signatures in gynecological tumor cell lines reflected those detected in primary tumors. CONCLUSIONS: Taken together, these analyses indicate that application of mutation signature analysis not only advances our understanding of mutational processes and their interactions, but also it has the potential to stratify patients that could benefit from treatments available for tumors harboring distinct mutational signatures and to improve clinical decision-making for gynecological malignancies.

RNA sequencing identifies clonal structure of T-cell repertoires in patients with adult T-cell leukemia/lymphoma.

The diversity of T-cell receptor (TCR) repertoires, as generated by somatic DNA rearrangements, is central to immune system function. High-throughput sequencing technologies now allow examination of antigen receptor repertoires at single-nucleotide and, more recently, single-cell resolution. The TCR repertoire can be altered in the context of infections, malignancies or immunological disorders. Here we examined the diversity of TCR clonality and its association with pathogenesis and prognosis in adult T-cell leukemia/lymphoma (ATL), a malignancy caused by infection with human T-cell leukemia virus type-1 (HTLV-1). We analyzed 62 sets of high-throughput RNA sequencing data from 59 samples of HTLV-1-infected individuals-asymptomatic carriers (ACs), smoldering, chronic, acute and lymphoma ATL subtypes-and three uninfected controls to evaluate TCR distribution. Based on these TCR profiles, CD4-positive cells and ACs showed polyclonal patterns, whereas ATL patients showed oligo- or monoclonal patterns (with 446 average clonotypes across samples). Expression of TCRα and TCRß genes in the dominant clone differed among the samples. ACs, CD4-positive samples and smoldering patients showed significantly higher TCR diversity compared with chronic, acute and lymphoma subtypes. CDR3 sequence length distribution, amino acid conservation and gene usage variability for ATL patients resembled those of peripheral blood cells from ACs and healthy donors. Thus, determining monoclonal architecture and clonal diversity by RNA sequencing might be useful for prognostic purposes and for personalizing ATL diagnosis and assessment of treatments.

Mutational Intratumor Heterogeneity is a Complex and Early Event in the Development of Adult T-cell Leukemia/Lymphoma.

The clonal architecture of tumors plays a vital role in their pathogenesis and invasiveness; however, it is not yet clear how this clonality contributes to different malignancies. In this study we sought to address mutational intratumor heterogeneity (ITH) in adult T-cell leukemia/lymphoma (ATL). ATL is a malignancy with an incompletely understood molecular pathogenesis caused by infection with human T-cell leukemia virus type-1 (HTLV-1). To determine the clonal structure through tumor genetic diversity profiles, we investigated 142 whole-exome sequencing data of tumor and matched normal samples from 71 ATL patients. Based on SciClone analysis, the ATL samples showed a wide spectrum of modes over clonal/subclonal frequencies ranging from one to nine clusters. The average number of clusters was six across samples, but the number of clusters differed among different samples. Of these ATL samples, 94% had more than two clusters. Aggressive ATL cases had slightly more clonal clusters than indolent types, indicating the presence of ITH during earlier stages of disease. The known significantly mutated genes in ATL were frequently clustered together and possibly coexisted in the same clone. IRF4, CCR4, TP53, and PLCG1 mutations were almost clustered in subclones with a moderate variant allele frequency (VAF), whereas HLA-B, CARD11, and NOTCH1 mutations were clustered in subclones with lower VAFs. Taken together, these results show that ATL displays a high degree of ITH and a complex subclonal structure. Our findings suggest that clonal/subclonal architecture might be a useful measure for prognostic purposes and personalized assessment of the therapeutic response.

Industry-university collaborations in Canada, Japan, the UK and USA--with emphasis on publication freedom and managing the intellectual property lock-up problem.

As industry-university collaborations are promoted to commercialize university research and foster economic growth, it is important to understand how companies benefit from these collaborations, and to ensure that resulting academic discoveries are developed for the benefit of all stakeholders: companies, universities and public. Lock up of inventions, and censoring of academic publications, should be avoided if feasible. This case-study analysis of interviews with 90 companies in Canada, Japan, the UK and USA assesses the scope of this challenge and suggests possible resolutions. The participating companies were asked to describe an important interaction with universities, and most described collaborative research. The most frequently cited tensions concerned intellectual property management and publication freedom. IP disagreements were most frequent in the context of narrowly-focused collaborations with American universities. However, in the case of exploratory research, companies accepted the IP management practices of US universities. It might make sense to let companies have an automatic exclusive license to IP from narrowly defined collaborations, but to encourage universities to manage inventions from exploratory collaborations to ensure development incentives. Although Canada, the UK and US have strong publication freedom guarantees, tensions over this issue arose frequently in focused collaborations, though were rare in exploratory collaborations. The UK Lambert Agreements give sponsors the option to control publications in return for paying the full economic cost of a project. This may offer a model for the other three countries. Uniquely among the four countries, Japan enables companies to control exclusively most collaborative inventions and to censor academic publications. Despite this high degree of control, the interviews suggest many companies do not develop university discoveries to their full potential. The steps suggested above may rebalance the situation in Japan. Overall, the interviews reveal the complexity of these issues and the need for flexibility on the part of universities and companies.

The importance of new companies for drug discovery: origins of a decade of new drugs.

Understanding the factors that promote drug innovation is important both for improvements in health care and for the future of organizations engaged in drug discovery research and development. By identifying the inventors of 252 new drugs approved by the US Food and Drug Administration from 1998 to 2007 and their places of work, and also classifying these drugs according to innovativeness, this study investigates the contribution of different types of organizations and regions to drug innovation during this period. The data indicate that drugs initially discovered in biotechnology companies or universities accounted for approximately half of the scientifically innovative drugs approved, as well as half of those that responded to unmet medical needs, although their contribution to the total number of new drugs was proportionately lower. The biotechnology companies were located mainly in the United States. This article presents a comprehensive analysis of these data and discusses potential contributing factors to the trends observed, with the aim of aiding efforts to promote drug innovation.