Hypoxia, or gradients of hypoxia, occurs in most growing solid tumors and may result in pleotropic effects contributing significantly to tumor aggressiveness and therapy resistance. Indeed, the generated hypoxic stress has a strong impact on tumor cell biology. For example, it may contribute to increasing tumor heterogeneity, help cells gain new functional properties and/or select certain cell subpopulations, facilitating the emergence of therapeutic resistant cancer clones, including cancer stem cells coincident with tumor relapse and progression. It controls tumor immunogenicity, immune plasticity, and promotes the differentiation and expansion of immune-suppressive stromal cells. In this context, manipulation of the hypoxic microenvironment may be considered for preventing or reverting the malignant transformation. Here, we review the current knowledge on how hypoxic stress in tumor microenvironments impacts on tumor heterogeneity, plasticity and resistance, with a special interest in the impact on immune resistance and tumor immunogenicity.

Human mitochondrial DNA haplogroup U is among the initial maternal founders in Southwest Asia and Europe and one that best indicates matrilineal genetic continuity between late Pleistocene hunter-gatherer groups and present-day populations of Europe. While most haplogroup U subclades are older than 30 thousand years, the comparatively recent coalescence time of the extant variation of haplogroup U7 (~16–19 thousand years ago) suggests that its current distribution is the consequence of more recent dispersal events, despite its wide geographical range across Europe, the Near East and South Asia. Here we report 267 new U7 mitogenomes that – analysed alongside 100 published ones – enable us to discern at least two distinct temporal phases of dispersal, both of which most likely emanated from the Near East. The earlier one began prior to the Holocene (~11.5 thousand years ago) towards South Asia, while the later dispersal took place more recently towards Mediterranean Europe during the Neolithic (~8 thousand years ago). These findings imply that the carriers of haplogroup U7 spread to South Asia and Europe before the suggested Bronze Age expansion of Indo-European languages from the Pontic-Caspian Steppe region.

TCAP encoded telethonin is a 19 kDa protein, which plays an important role in anchoring titin in Z disc of the sarcomere, and is known to cause LGMD2G, a rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. A total of 300 individuals with ARLGMD were recruited for this study. Among these we identified 8 clinically well characterised LGMD2G cases from 7 unrelated Dravidian families. Clinical examination revealed predominantly proximo - distal form of weakness, scapular winging, muscle atrophy, calf hypertrophy and foot drop, immunoblot showed either complete absence or severe reduction of telethonin. Genetic analysis revealed a novel nonsense homozygous mutation c.32C>A, p.(Ser11*) in three patients of a consanguineous family and an 8 bp homozygous duplication c.26_33dupAGGTGTCG, p.(Arg12fs31*) in another patient. Both mutations possibly lead to truncated protein or nonsense mediated decay. We could not find any functionally significant TCAP mutation in the remaining 6 samples, except for two other polymorphisms, c.453A>C, p.( = ) and c.-178G>T, which were found in cases and controls. This is the first report from India to demonstrate TCAP association with LGMD2G.

Tumor hypoxia-induced downregulation of DNA repair pathways and enhanced replication stress are potential sources of genomic instability. A plethora of genetic changes such as point mutations, large deletions and duplications, microsatellite and chromosomal instability have been discovered in cells under hypoxic stress. However, the influence of hypoxia on the mutational burden of the genome is not fully understood. Here, we attempted to elucidate the DNA damage response and repair patterns under different types of hypoxic stress. In addition, we examined the pattern of mutations exclusively induced under chronic and intermittent hypoxic conditions in two breast cancer cell lines using exome sequencing. Our data indicated that hypoxic stress resulted in transcriptional downregulation of DNA repair genes which can impact the DNA repair induced during anoxic as well as reoxygenated conditions. In addition, our findings demonstrate that hypoxic conditions increased the mutational burden, characterized by an increase in frameshift insertions and deletions. The somatic mutations were random and non-recurring, as huge variations within the technical duplicates were recognized. Hypoxia also resulted in an increase in the formation of potential neoantigens in both cell lines. More importantly, these data indicate that hypoxic stress mitigates DNA damage repair pathways and causes an increase in the mutational burden of tumor cells, thereby interfering with hypoxic cancer cell immunogenicity.