A Pathogenic Variant Reclassified to the Pseudogene PMS2P1 in a Patient with Suspected Hereditary Cancer.

The PMS2 gene is involved in DNA repair by the mismatch repair pathway. Deficiencies in this mechanism have been associated with Lynch Syndrome (LS), which is characterized by a high risk for colorectal, endometrial, ovarian, breast, and other cancers. Germinal pathogenic variants of PMS2 are associated with up to 5% of all cases of LS. The prevalence is overestimated for the existence of multiple homologous pseudogenes. We report the case of a 44-year-old woman diagnosed with breast cancer at 34 years without a relevant cancer family history. The presence of pathogenic variant NM_000535.7:c.1A > T, (p.Met1Leu) in PMS2 was determined by next-generation sequencing analysis with a panel of 322 cancer-associated genes and confirmed by capillary sequencing in the patient. The variant was determined in six family members (brothers, sisters, and a son) and seven non-cancerous unrelated individuals. Analysis of the amplified region showed high homology of PMS2 with five of its pseudogenes. We determined that the variant is associated with the PMS2P1 pseudogene following sequence alignment analysis. We propose considering the variant c.1A > T, (p.Met1Leu) in PMS2 for reclassification as not hereditary cancer-related, given the impact on the diagnosis and treatment of cancer patients and families carrying this variant.

A Previously Unrecognized Molecular Landscape of Lynch Syndrome in the Mexican Population.

Lynch syndrome (LS) is the main hereditary colorectal cancer syndrome. There have been few reports regarding the clinical and molecular characteristics of LS patients in Latin America; this is particularly true in the Mexican population, where no information is available. The present study aims to describe the clinical and molecular spectrum of variants in a cohort of patients diagnosed with LS in Mexico. We present a retrospective analysis of 412 patients with suspected LS, whose main site of cancer diagnosis was the colon (58.25%), followed by the endometrium (18.93%). Next-generation sequencing analysis, with an extensive multigene panel, showed that 27.1% (112/414) had a variant in one of the genes of the mismatch repair pathway (MMR); 30.4% (126/414) had a variant in non-MMR genes such as CHEK2, APC, MUTYH, BRCA1, and BRCA2; and 42.5% (176/414) had no genetic variants. Most of the variants were found in MLH1. Pathogenic variants (PVs) in MMR genes were identified in 65.7% (96/146) of the total PVs, and 34.24% (45/146) were in non-MMR genes. Molecular and clinical characterization of patients with LS in specific populations allowed personalized follow-up, with the option for targeted treatment with immune checkpoint inhibitors and the development of public health policies. Moreover, such characterization allows for family cascade testing and consequent prevention strategies.

Molecular changes in adipocyte-derived stem cells during their interplay with cervical cancer cells.

PURPOSE: Obesity is as an important risk factor and has been associated with a worse prognosis in at least 13 distinct tumor types. This is partially due to intercellular communication between tumor cells and adipose tissue-derived stem cells (ADSCs), which are increased in obese individuals. As yet, however, little is known about the molecular changes occurring in ADSCs in these conditions. Cervical cancer has a high incidence and mortality rate in women from developing countries, particularly in those with a high body mass index (BMI). METHODS: We analyzed the expression profile of ADSCs co-cultured with cervical cancer cells through massive RNA sequencing followed by evaluation of various functional alterations resulting from the modified transcriptome. RESULTS: A total of 761 coding and non-coding dysregulated RNAs were identified in ADSCs after co-culture with HeLa cells (validation in CaSki and SiHA cells). Subsequent network analysis showed that these changes were correlated with migration, stemness, DNA repair and cytokine production. Functional experiments revealed a larger ALDHhigh subpopulation and a higher migrative capacity of ADSCs after co-culture with HeLa cells. Interestingly, CXCL3 and its intragenic long-noncoding RNA, lnc-CXCL3, were found to be co-regulated during co-culture. A loss-of-function assay revealed that lnc-CXCL3 acts as a key regulator of CXCL3 expression. CONCLUSIONS: Our results suggest that intercellular communication between ADSCs and cervical cancer cells modifies the RNA expression profile in the former, including that of lncRNAs, which in turn can regulate the expression of diverse chemokines that favor malignancy-associated capacities such as migration.

lncRNAs in mesenchymal differentiation.

In recent years, technological advances have revealed a large potential number of long noncoding RNAs (lncRNAs). Findings recognize lncRNAs as orchestrating molecules in a wide range of processes, at the transcriptional and posttranscriptional levels, although fewer studies address function. For differentiation, which consists of rearrangements in the gene expression profile and activation of stage- and cell type-dependent signaling mechanisms, the relevance of lncRNAs becomes crucial. The relationship between lncRNAs and key molecular factors in differentiation is strengthening; therefore the present review aims to comprehensively explain the role of lncRNAs in the signaling network involved in the main types of mesenchymal differentiation: adipogenesis, chondrogenesis, myogenesis, and osteogenesis. Notably, a step toward the integration of lncRNAs in the field of cell differentiation promises an exceptional impact.

Challenges of diagnostic genomics in Latin America.

Cancer genome sequencing methods have now become essential for diagnostic purposes, for devising treatment strategies, and for monitoring disease regression and progression. However, access to these benefits has not permeated homogeneously throughout the world; certain regions, such as Latin America, have been slower at adopting these technologies in terms of their routine use, development and patient access. There are also differences among Latin American subregions with respect to their prioritized types of neoplasia and the drugs that are available and approved in them. An overview of the current situation, including the status of genomics for cancer diagnostics and efforts by type of cancer is presented. In addition, we discuss the perspective of initiatives, alliances, and educational/research programs that pledge to make cancer genomics diagnosis a reality for Latin American individuals' health.