For the last 500 years, the Americas have been a melting pot both for genetically diverse humans and for the pathogenic and commensal organisms associated with them. One such organism is the stomach-dwelling bacterium Helicobacter pylori, which is highly prevalent in Latin America where it is a major current public health challenge because of its strong association with gastric cancer. By analyzing the genome sequence of H. pylori isolated in North, Central and South America, we found evidence for admixture between H. pylori of European and African origin throughout the Americas, without substantial input from pre-Columbian (hspAmerind) bacteria. In the US, strains of African and European origin have remained genetically distinct, while in Colombia and Nicaragua, bottlenecks and rampant genetic exchange amongst isolates have led to the formation of national gene pools. We found three outer membrane proteins with atypical levels of Asian ancestry in American strains, as well as alleles that were nearly fixed specifically in South American isolates, suggesting a role for the ethnic makeup of hosts in the colonization of incoming strains. Our results show that new H. pylori subpopulations can rapidly arise, spread and adapt during times of demographic flux, and suggest that differences in transmission ecology between high and low prevalence areas may substantially affect the composition of bacterial populations.
Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer.
Helicobacter pylori (HP) genetics may determine its clinical outcomes. Despite high prevalence of HP infection in Latin America (LA), there have been no phylogenetic studies in the region. We aimed to understand the structure of HP populations in LA mestizo individuals, where gastric cancer incidence remains high. The genome of 107 HP strains from Mexico, Nicaragua and Colombia were analyzed with 59 publicly available worldwide genomes. To study bacterial relationship on whole genome level we propose a virtual hybridization technique using thousands of high-entropy 13 bp DNA probes to generate fingerprints. Phylogenetic virtual genome fingerprint (VGF) was compared with Multi Locus Sequence Analysis (MLST) and with phylogenetic analyses of cagPAI virulence island sequences. With MLST some Nicaraguan and Mexican strains clustered close to Africa isolates, whereas European isolates were spread without clustering and intermingled with LA isolates. VGF analysis resulted in increased resolution of populations, separating European from LA strains. Furthermore, clusters with exclusively Colombian, Mexican, or Nicaraguan strains were observed, where the Colombian cluster separated from Europe, Asia, and Africa, while Nicaraguan and Mexican clades grouped close to Africa. In addition, a mixed large LA cluster including Mexican, Colombian, Nicaraguan, Peruvian, and Salvadorian strains was observed; all LA clusters separated from the Amerind clade. With cagPAI sequence analyses LA clades clearly separated from Europe, Asia and Amerind, and Colombian strains formed a single cluster. A NeighborNet analyses suggested frequent and recent recombination events particularly among LA strains. Results suggests that in the new world, H. pylori has evolved to fit mestizo LA populations, already 500 years after the Spanish colonization. This co-adaption may account for regional variability in gastric cancer risk.
The serologic response against virus-like particles (VLP) from 7 high risk genital papillomaviruses was investigated by ELISA in 147 Colombian women with invasive cervical cancer and 147 age-matched cytologically normal and HPV-DNA negative women. Anti-VLP antibodies were detected in 82% of the invasive cervical cancer patients and in 56% of the controls. Detection of antibodies against multiple HPV types is the rule and the presence of high antibody titers was associated with higher survival of cancer patients. Higher anti-VLP seroprevalence was observed in younger cancer patients. In those followed serologically for 1 year, antibodies generally remained at the same level. However, in some patients an increase or decrease in antibody levels occurred simultaneously for multiple HPV types, suggesting cross-reactivity between the HPV types investigated. Investigation of seroreactivity between 8 high risk HPVs suggested that there is some cross-reactivity between phylogeneticaly-related types such as 16, 31, 33 and 58; and 18, 45 and 59. In conclusion, our results confirmed (i) the high rate of HPV infections in Colombia, both in patients with cervical cancer and in the general population, and the particularly high rate of infections due to HPV 31 and 58; and (ii) the validity of anti-VLPs as a marker of present or past HPV infection. The simultaneous appearance or disappearance of antibodies against multiple HPV VLPs suggests that the antibodies detected by ELISA are not always type specific. © 2002 Wiley-Liss, Inc. Key words: HPV; virus-like particles; cervical cancer; anti-VLP antibodiesCancer of the uterine cervix is one of the most common malignancies in women world wide. 1,2 and the contribution of high risk or oncogenic genital human papillomaviruses (HPVs) in the development of such cancers is well established. [3][4][5][6] Cohort studies indicate that HPV infection with oncogenic types is mostly transient and that only a small proportion of those infected become carriers and then develop cervical intraepithelial neoplasia. [7][8][9][10][11][12] Over 100 HPV genotypes have been identified, 6,13 of which approximately 40 types infect the anogenital tract. The etiologic role of papillomavirus in cervical cancer has been recognized for only a limited number of them, including in decreasing order. 14 The geographical distribution of oncogenic HPV types in cervical cancers shows that HPV-16 is the most common type in all regions, followed by HPV-18. However, there are some geographical differences. For example HPV-33, -39, -58 and -59 are more common in Latin America than in other regions. 4,12,15 Colombia has one of the highest incidences of cervical cancer in the world (48 cases/ 100,000 women/year 1 ) and the most common types detected in Colombia are HPV-16, followed by HPV 58. 16,17 Numerous serologic studies using mainly HPV-16 VLPs 18 -27 have demonstrated that infection with genital HPVs is followed by a serologic immune response to viral capsid proteins and that anti-VLP antibodies can be an indicat...
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