INTRODUCTION To date, 559 humans have been flown into space, but long-duration (>300 days) missions are rare (n = 8 total). Long-duration missions that will take humans to Mars and beyond are planned by public and private entities for the 2020s and 2030s; therefore, comprehensive studies are needed now to assess the impact of long-duration spaceflight on the human body, brain, and overall physiology. The space environment is made harsh and challenging by multiple factors, including confinement, isolation, and exposure to environmental stressors such as microgravity, radiation, and noise. The selection of one of a pair of monozygotic (identical) twin astronauts for NASA’s first 1-year mission enabled us to compare the impact of the spaceflight environment on one twin to the simultaneous impact of the Earth environment on a genetically matched subject. RATIONALE The known impacts of the spaceflight environment on human health and performance, physiology, and cellular and molecular processes are numerous and include bone density loss, effects on cognitive performance, microbial shifts, and alterations in gene regulation. However, previous studies collected very limited data, did not integrate simultaneous effects on multiple systems and data types in the same subject, or were restricted to 6-month missions. Measurement of the same variables in an astronaut on a year-long mission and in his Earth-bound twin indicated the biological measures that might be used to determine the effects of spaceflight. Presented here is an integrated longitudinal, multidimensional description of the effects of a 340-day mission onboard the International Space Station. RESULTS Physiological, telomeric, transcriptomic, epigenetic, proteomic, metabolomic, immune, microbiomic, cardiovascular, vision-related, and cognitive data were collected over 25 months. Some biological functions were not significantly affected by spaceflight, including the immune response (T cell receptor repertoire) to the first test of a vaccination in flight. However, significant changes in multiple data types were observed in association with the spaceflight period; the majority of these eventually returned to a preflight state within the time period of the study. These included changes in telomere length, gene regulation measured in both epigenetic and transcriptional data, gut microbiome composition, body weight, carotid artery dimensions, subfoveal choroidal thickness and peripapillary total retinal thickness, and serum metabolites. In addition, some factors were significantly affected by the stress of returning to Earth, including inflammation cytokines and immune response gene networks, as well as cognitive performance. For a few measures, persistent changes were observed even after 6 months on Earth, including some genes’ expression levels, increased DNA damage from chromosomal inversions, increased numbers of short telomeres, and attenuated cognitive function. CONCLUSION Given that the majority of the biological and human health variables remained stable, or returned to baseline, after a 340-day space mission, these data suggest that human health can be mostly sustained over this duration of spaceflight. The persistence of the molecular changes (e.g., gene expression) and the extrapolation of the identified risk factors for longer missions (>1 year) remain estimates and should be demonstrated with these measures in future astronauts. Finally, changes described in this study highlight pathways and mechanisms that may be vulnerable to spaceflight and may require safeguards for longer space missions; thus, they serve as a guide for targeted countermeasures or monitoring during future missions.

The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight.

Genomic Evolution of Breast Cancer Metastasis and Relapse

Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR-Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair–deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations.

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Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer.

Environmental chemicals and breast cancer: An updated review of epidemiological literature informed by biological mechanisms.

Somatic mutations in cancer genomes are caused by multiple mutational processes each of which generates a characteristic mutational signature. Using 84,729,690 somatic mutations from 4,645 whole cancer genome and 19,184 exome sequences encompassing most cancer types we characterised 49 single base substitution, 11 doublet base substitution, four clustered base substitution, and 17 small insertion and deletion mutational signatures. The substantial dataset size compared to previous analyses enabled discovery of new signatures, separation of overlapping signatures and decomposition of signatures into components that may represent associated, but distinct, DNA damage, repair and/or replication mechanisms. Estimation of the contribution of each signature to the mutational catalogues of individual cancer genomes revealed associations with exogenous and endogenous exposures and defective DNA maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes contributing to the development of human cancer including a comprehensive reference set of mutational signatures in human cancer.

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The Repertoire of Mutational Signatures in Human Cancer

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.

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Susan Merson

Papers

Mutational signatures of ionizing radiation in second malignancies.