DNA sensing in cancer: Pro-tumour and anti-tumour functions of cGAS-STING signalling.

The DNA sensor cGAS (cyclic GMP-AMP synthase) and its adaptor protein STING (Stimulator of Interferon Genes) detect the presence of cytosolic DNA as a sign of infection or damage. In cancer cells, this pathway can be activated through persistent DNA damage and chromosomal instability, which results in the formation of micronuclei and the exposure of DNA fragments to the cytosol. DNA damage from radio- or chemotherapy can further activate DNA sensing responses, which may occur in the cancer cells themselves or in stromal and immune cells in the tumour microenvironment (TME). cGAS-STING signalling results in the production of type I interferons, which have been linked to immune cell infiltration in 'hot' tumours that are susceptible to immunosurveillance and immunotherapy approaches. However, recent research has highlighted the complex nature of STING signalling, with tumours having developed mechanisms to evade and hijack this signalling pathway for their own benefit. In this mini-review we will explore how cGAS-STING signalling in different cells in the TME can promote both anti-tumour and pro-tumour responses. This includes the role of type I interferons and the second messenger cGAMP in the TME, and the influence of STING signalling on local immune cell populations. We examine how alternative signalling cascades downstream of STING can promote chronic interferon signalling, the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of inflammatory cytokines, which can have pro-tumour functions. An in-depth understanding of DNA sensing in different cell contexts will be required to harness the anti-tumour functions of STING signalling.

X chromosome-inactivation patterns in patients with Rett syndrome.

Rett syndrome (RS) is a complex and severely disabling neurologic disorder, restricted to females. As non-random X inactivation could indicate that the X chromosome has a role in the etiology of the syndrome, we performed molecular analysis based on the differential methylation of the active and inactive X chromosomes with probe M27beta, taking into account the parental origin of the two Xs, in 24 RS girls (including a pair of concordant monozygote twins), 22 mothers, and a control group of 30 normal women. The results showed a significantly (Fisher's exact test) increased frequency of skewed X inactivation in lymphocytes from 15/23 RS compared with 4/22 mothers (P = 0.0031) and 6/30 controls (P = 0.0021). Our results, together with those from the literature, showed that as a group, RS patients are apparently more prone to skewed X inactivation than their mothers and normal controls, and this suggests that the X chromosome is somehow involved in RS etiology.

In search of a genetic basis for the Rett syndrome.

Rett syndrome is a progressive encephalopathy restricted to the female sex. In the present paper a possible genetic cause for this syndrome is discussed, based on data from the literature as well as our own. Our results are in agreement with others regarding no increase in parental age, or in spontaneous abortions rate among the mothers of affected children and with a normal sex ratio among sibs. We have found no chromosome rearrangement detectable with the methods used and no correlation between fra(X) (p22) and the Rett syndrome. We have observed an alteration in the sequence of replication in one of the two types of late-replicating X-chromosome present in normal women, and suggest that this may signify that genes which are active in the late-replicating X-chromosome are inactivated (or vice-versa) in these patients. This fact could be related to the abnormal phenotype observed in Rett syndrome patients.

What causes the abnormal phenotype in a 49,XXXXY male?

The chromosome replication pattern of a man with 49,XXXXY was analyzed using 3H-thymidine and autoradiography as well as BrdU and acridine orange. The former technique showed a highly irregular replication pattern; the latter revealed one early replicating X chromosome, and the other three more or less asynchronously replicating. Two hypotheses seem to explain best the abnormal phenotype of males with an XXXXY sex chromosome constitution: The number of the always active regions (tip of Xp) and of the possibly always active regions (the Q-dark regions on both sides of the centromere) is increased from one to four. The replication pattern of the late-replicating X chromosomes is highly asynchronous, which might affect the phenotype. The possibility that more than one X chromosome might remain active in some cells, an even more abnormal and obviously deleterious situation, is still open.

Brief clinical report: autosomal recessive anophthalmia with multiple congenital abnormalities--type Waardenburg.

We report two Brazilian families with children who had anophthalmia and multiple congenital abnormalities and consanguineous parents. Among the five affected children, four had bilateral and one had unilateral anophthalmia. Autosomal recessive inheritance is demonstrated.

Partial trisomy 18q and partial monosomy 13q resulting from a paternal 13 / 18 translocation

E descrita uma paciente portadora de trissomia parcial 18q22 - 18qter e de provavel monossomia parcial 13q-34qter. O fenotipo resultante e comparado com o da trissomia 18 e com o de outros casos portadores de trissomia parcial 18q e monosomia parcial 13q

Spontaneous cell fusion and PCC formation in Bloom's syndrome.

Corresponding to 4,633 diploid lymphocytes 64 tetraploid or near-tetraploid (including one octoploid) metaphases were found in two sibs with Bloom's syndrome. Eight of the polyploid cells had resulted from cell fusion with half the chromosomes representing PCC. One similar fibroblast was also observed. In 13,584 untreated cells from persons without a chromosome-breakage syndrome no such cells were encountered (P = 0.0000176). This seems to be the first description of spontaneous fusion of nonmalignant cells. The extended segments in the G2 type PCC which correspond to the Q-bright, late-replicating chromosome parts are less tightly spiralized than other chromosome regions which renders the chromosomes similar to those which have incorporated BrdU late in the S period. Obviously the chromosome segments which replicate last also are the last to spiralize.

The behavior of allocyclic chromosomes in Bloom's syndrome.

The behavior of individual allocyclic chromosomes has been analyzed in lymphocytes of a sister and a brother with Bloom's syndrome. Of 4,633 46 diploid cells, 115 showed allocyclic chromosomes, and 74 of these had 44, 45 or 46 normal metaphase chromosomes accompanied by one or two allocyclic chromosomes. Of 56 tetraploid cells, 9 contained such chromosomes. The allocyclic chromosomes appeared "pulverized" or extended corresponding to S or G2 PCC. We have proposed the hypothesis that individual allocyclic chromosomes do not, as a rule, come from micronuclei, as has often been assumed, but have been left behind in their cycle. This would be caused by a mutation or deletion of a hypothetical coiling center situated near the centromere of each chromosome arm. The following observations agree with our explanation but less well or not at all with the idea of micronuclei: (1) In only 9.6% of the cells does the allocyclic chromosome lie at the edge of the metaphase plate. (2) In 24 cells a part of a chromosome is "pulverized" while the rest is in metaphase. (3) Both a "pulverized" and an extended chromosome were present in the same cell. (4) A "pulverized" acrocentric is often nose-to-nose with a normal D or G chromosome. (5) No allocyclic chromosomes corresponding to G1 PCC have been found in our material. (6) When a ring is replaced by an allocyclic chromosome, it is usually a member of a 46-chromosome complement. Furthermore, the occurrence of allocyclic chromosomes is correlated with that of other chromosome anomalies which do not follow a Poisson distribution. Allocyclic chromosomes are also more frequent (16%) in tetraploid than in diploid cells (2%).

Mitotic recombination and segregation of satellites in Bloom's syndrome.

Mitotic recombination in satellite stalks--a phenomenon often difficult to distinguish from satellite association--was studied in a sister and a brother with Bloom's syndrome. Segregation after recombination was analyzed in the lymphocytes of the sister who had Q-bright satellites. Her cells varied greatly both in regard to the acrocentrics which displayed Q-bright satellites and the number of such satellites per cell. In 58 cells a total of 31 different patterns were seen. In 83 cells of 6 controls who also had Q-bright satellites on at least one acrocentric chromosome, not one cell was found in which the pattern differed from that characteristic of the person. Obviously exchanges between satellite stalks in patients with Bloom's syndrome are fairly frequent (estimated lower limit 6/1000) and very rare in persons who do not have this syndrome (estimated 0.1/1000).

H-Y antigen expression in a case of mixed gonadal dysgenesis.

H-Y antigen expression was studied on leukocytes and gonad-derived fibroblasts from a patient affected by mixed gonadal dysgenesis. Blood leukocytes and fibroblasts derived from the testis were typed H-Y positive, but the fibroblasts derived from the streak gonad were H-Y negative. Although the patient's karyotype was a mosaic, 45,XO/46,X+mar, as detected in-peripheral blood cells and testis-derived fibroblasts, all the fibroblasts derived from the streak gonad were 45,XO. These data suggests that the marker chromosome was in fact a Y-derived chromosome. Moreover, they showed that, at the gonadal level, a minority of H-Y positive 46,X+mar cells were able to organize a testis. Nevertheless, a large number of XO cells probably did not receive the testicular forming influence of the H-Y antigen and of the other masculinizing factors.

H-Y antigen expression in a case of XX true hermaphroditism.

Cells from an XX true hermaphrodite expressed a reduced amount of H-Y antigen when compared with normal XY cells and with cells from his father, who had an XY/XX chromosomal constitution. His mother had a normal karyotype and was H-Y negative. The four brothers of the patient were clinically and karyotypically normal. An X-Y interchange followed by random inactivation of the X chromosome is proposed to explain the H-Y antigen titer found in the patient.

The importance of A'-d ridge count in dermatoglyphic diagnosis of the Ullrich-Turner syndrome.

The dermatoglyphic characteristics of 52 women with the Ullrich-Turner syndrome were studied and compared to those of a control group of 50 normal women. Through the use of discriminant analysis, it is shown that the use of the A'-d ridge count alone has the same efficiency in separating Ullrich-Turner syndrome patients from normal female subjects as discriminant functions here derived and other methods already published in the literature.

H-Y gene expression in apparent absence of the long arm of the Y chromosome.

H-Y antigen expression was detected on cells from an individual having a presumptive 45,X/46,X,i(Yp) karyotype, but was absent on cells from another person having a 46,X,i(Yq) karyotype. This suggests that the short arm of the human Y chromosome is essential for H-Y antigen expression, at least in the subjects studied.

Partial monosomy 13 and 21 due to a familial 13/21 translocation.

Two patients are described with a monosomy for the proximal part of the long are of chromosome 13 and for the distal part of the long arm of chromosome 21, due to an unbalanced 13/21 translocation.