Three synchronous primary carcinomas in a patient with HNPCC associated with a novel germline mutation in MLH1: Case report

<p>Abstract</p> <p>Background</p> <p><it>MLH1 </it>is one of six known genes responsible for DNA mismatch repair (MMR), whose inactivation leads to HNPCC. It is important to develop genotype-phenotype correlations for HNPCC, as is being done for other hereditary cancer syndromes, in order to guide surveillance and treatment strategies in the future.</p> <p>Case presentation</p> <p>We report a 47 year-old male with hereditary nonpolyposis colorectal cancer (HNPCC) associated with a novel germline mutation in <it>MLH1</it>. This patient expressed a rare and severe phenotype characterized by three synchronous primary carcinomas: ascending and splenic flexure colon adenocarcinomas, and ureteral carcinoma. Ureteral neoplasms in HNPCC are most often associated with mutations in <it>MSH2 </it>and rarely with mutations in <it>MLH1</it>. The reported mutation is a two base pair insertion into exon 10 (c.866_867insCA), which results in a premature stop codon.</p> <p>Conclusion</p> <p>Our case demonstrates that HNPCC patients with <it>MLH1 </it>mutations are also at risk for ureteral neoplasms, and therefore urological surveillance is essential. This case adds to the growing list of disease-causing MMR mutations, and contributes to the development of genotype-phenotype correlations essential for assessing individual cancer risk and tailoring of optimal surveillance strategies. Additionally, our case draws attention to limitations of the Amsterdam Criteria and the need to maintain a high index of suspicion when newly diagnosed colorectal cancer meets the Bethesda Criteria. Establishment of the diagnosis is the crucial first step in initiating appropriate surveillance for colorectal cancer and other HNPCC-associated tumors in at-risk individuals.</p

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

In-house trauma attendings: a new financial benefit for hospitals

There is an intuitive belief that in-house trauma attendings benefit patient outcome, although multiple studies have failed to prove this. However, no studies investigate the financial advantage for hospitals by having the attendings also perform urgent general surgery cases (GSC) during nights and weekends. The purpose of this study is to identify how an in-house attending program was used for urgent GSC and to see if it provided a financial benefit to the hospital. The in-house program began in October 2007. A retrospective study reviewed all cholecystectomies performed from October 2006 to September 2007 and October 2007 to September 2008. Total length of stay (LOS) was calculated. Total LOS for each group was multiplied by the daily cost for a medical-surgical bed ($2,530.00). The cost difference was calculated for the pre- and post-in-house groups. Two hundred sixty-four cholecystectomies were performed before instituting an in-house attending program compared with 291 cases in the period after a 9$16,192.00 in room costs versus 5.24 days after and $13,257.20 in room costs. This translated to a savings of$2,934.80 per patient and $854,026.80 savings in total because of reduced LOS, which subsidized the cost of the program, which was$750,000.00. In-house attendings are beneficial in decreasing overall LOS for urgent GSC. This study demonstrates that in-house attendings can perform urgent GSCs and realize a savings for a hospital that can be used to fully subsidize the cost of the program