Spatial mutation patterns as markers of early colorectal tumor cell mobility

A growing body of evidence suggests that a subset of human cancers grows as single clonal expansions. In such a nearly neutral evolution scenario, it is possible to infer the early ancestral tree of a full-grown tumor. We hypothesized that early tree reconstruction can provide insights into the mobility phenotypes of tumor cells during their first few cell divisions. We explored this hypothesis by means of a computational multiscale model of tumor expansion incorporating the glandular structure of colorectal tumors. After calibrating the model to multiregional and single gland data from 19 human colorectal tumors using approximate Bayesian computation, we examined the role of early tumor cell mobility in shaping the private mutation patterns of the final tumor. The simulations showed that early cell mixing in the first tumor gland can result in side-variegated patterns where the same private mutations could be detected on opposite tumor sides. In contrast, absence of early mixing led to nonvariegated, sectional mutation patterns. These results suggest that the patterns of detectable private mutations in colorectal tumors may be a marker of early cell movement and hence the invasive and metastatic potential of the tumor at the start of the growth. In alignment with our hypothesis, we found evidence of early abnormal cell movement in 9 of 15 invasive colorectal carcinomas (“born to be bad”), but in none of 4 benign adenomas. If validated with a larger dataset, the private mutation patterns may be used for outcome prediction among screen-detected lesions with unknown invasive potential.

Mutations in CYP11B1 and Congenital Adrenal Hyperplasia in Moroccan Jews

Context: In Jews of Moroccan descent (MJ), the prevalence of steroid 11β-hydroxylase deficiency (11-OHD) is relatively high, with a carrier rate estimated as approximately one in 40. A single mutation in the CYP11B1 gene (encoding 11β-hydroxylase), R448H, was suggested to account for the disease alleles in this population. Study Subjects: We screened 236 healthy MJ for R448H. Results: Only two of the subjects screened were found to be carriers, suggesting that the R448H allele frequency is lower than was assumed previously. An R448H/R448C compound heterozygote patient, diagnosed with 11-OHD, was identified. However, a subsequent screen of MJ subjects for R448C failed to detect any carriers, suggesting that this was a private mutation of this family. Conclusion: The high incidence of 11-OHD in MJ, therefore, is only partially explained by the presence of R448H as a founder mutation.

Red Cell Membrane Disorders

Disorders of the erythrocyte membrane, including hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, and hereditary stomatocytosis, comprise an important group of inherited hemolytic anemias. These syndromes are characterized by marked clinical and laboratory heterogeneity. Recent molecular studies have revealed that there is also significant genetic heterogeneity in these disorders. This is particularly true for the spherocytosis syndromes where each kindred has a private mutation in one of the spherocytosis genes. Treatment with splenectomy is curative in most patients. Splenectomy via a laparoscopic approach has become the surgical method of choice. Growing recognition and understanding of the long-term risks and complications of splenectomy, including cardiovascular disease, thrombotic disorders, and pulmonary hypertension, and the emergence of penicillin-resistant pneumococci, a concern for infection in overwhelming postsplenectomy infection, have led to reevaluation of the role of splenectomy. Recent management guidelines acknowledge these important considerations when entertaining splenectomy and recommend detailed discussion between health care providers, patient, and family.