A Pathogenic Variant Reclassified to the Pseudogene <i>PMS2P1</i> 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

Mexican BRCA1 founder mutation: Shortening the gap in genetic assessment for hereditary breast and ovarian cancer patients.

The deletion of exons 9 to 12 of BRCA1 (9-12 del BRCA1) is considered a founder mutation in the Mexican population. We evaluate the usefulness of the target detection of 9-12 del BRCA1 as the first molecular diagnostic strategy in patients with Hereditary Breast and Ovarian Cancer (HBOC). We performed the genetic assessment of 637 patients with suspected HBOC. The region corresponding to the breakpoints for the 9-12 del BRCA1 was amplified by polymerase chain reaction (PCR). An analysis of the clinical data of the carriers and non-carriers was done, searching for characteristics that correlated with the deletion. The 9-12 del BRCA1 was detected in 5% of patients with suspected HBOC (30/637). In patients diagnosed with ovarian cancer, 13 of 30 were 9-12 del BRCA1 carriers, which represents 43%. We found a significant association between the 9-12 del BRCA1 carriers with triple negative breast cancer and high-grade papillary serous ovarian cancer. We concluded that the detection of the 9-12 del BRCA1 is useful as a first molecular diagnostic strategy in the Mexican population. In particular, it shortens the gap in genetic assessment in patients with triple negative breast cancer and ovarian cancer

Revealing the Molecular Portrait of Triple Negative Breast Tumors in an Understudied Population through Omics Analysis of Formalin-Fixed and Paraffin-Embedded Tissues

<div><p>Triple negative breast cancer (TNBC), defined by the lack of expression of the estrogen receptor, progesterone receptor and human epidermal receptor 2, is an aggressive form of breast cancer that is more prevalent in certain populations, in particular in low- and middle-income regions. The detailed molecular features of TNBC in these regions remain unexplored as samples are mostly accessible as formalin-fixed paraffin embedded (FFPE) archived tissues, a challenging material for advanced genomic and transcriptomic studies. Using dedicated reagents and analysis pipelines, we performed whole exome sequencing and miRNA and mRNA profiling of 12 FFPE tumor tissues collected from pathological archives in Mexico. Sequencing analyses of the tumor tissues and their blood pairs identified <i>TP53</i> and <i>RB1</i> genes as the most frequently mutated genes, with a somatic mutation load of 1.7 mutations/exome Mb on average. Transcriptional analyses revealed an overexpression of growth-promoting signals (EGFR, PDGFR, VEGF, PIK3CA, FOXM1), a repression of cell cycle control pathways (TP53, RB1), a deregulation of DNA-repair pathways, and alterations in epigenetic modifiers through miRNA:mRNA network de-regulation. The molecular programs identified were typical of those described in basal-like tumors in other populations. This work demonstrates the feasibility of using archived clinical samples for advanced integrated genomics analyses. It thus opens up opportunities for investigating molecular features of tumors from regions where only FFPE tissues are available, allowing retrospective studies on the search for treatment strategies or on the exploration of the geographic diversity of breast cancer.</p></div

PAM50 classification of TNBC samples.

<p>The hierarchically-clustered normalized expression values of the PAM50 classifier genes is shown for the 12 triple negative breast cancers (TNBCs) analyzed and the five centroids. The samples were classified according to their correlation with the PAM50 centroids. Red and blue boxes represent overexpressed and down-regulated genes, respectively.</p

Networks of connectivity between miRNA and mRNA.

<p>(A) Networks of (A) up-regulated miRNAs and down-regulated mRNAs, (B) down-regulated miRNAs and up-regulated mRNAs, identified in the TNBC samples (only high confident interactions and genes involved in cancer were selected).</p

Whole exome sequencing summary statistics.

<p>Whole exome sequencing summary statistics.</p

Summary results of whole exome sequencing for all matched samples (n = 12).

<p>Top panel, details of mutations found in tumors in each specific samples (blue squares are single-nucleotide variants (SNVs) and red squares are insertions and deletions (Indels). Right panel shows the mutations per exome, the amount of mutations in driving and DNA repair genes and total number of mutations per tumor. Lower panel shows gene annotations derived from present results and other studies: Recurrent gene mutated in more than one sample in present series; Mutated in triple negative breast cancer (TNBC) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126762#pone.0126762.ref007" target="_blank">7</a>], significantly mutated in TNBC from TCGA [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126762#pone.0126762.ref049" target="_blank">49</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126762#pone.0126762.ref050" target="_blank">50</a>]; Oncogenes and tumor suppressors class derived from references [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126762#pone.0126762.ref021" target="_blank">21</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126762#pone.0126762.ref051" target="_blank">51</a>]; Epigenetic modifiers class derived from references [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126762#pone.0126762.ref052" target="_blank">52</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126762#pone.0126762.ref053" target="_blank">53</a>]; Clinical target, genes that are targets of drugs in clinical trials or approved by FDA. (<a href="http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/default.htm" target="_blank">http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/default.htm</a>).</p