Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels Gastrointestinal Cancer

Purpose Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer (CRC). In metastatic CRC, sequencing of RAS/BRAF is necessary to guide clinical management. We hypothesized that a next-generation sequencing (NGS) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency (MMR-D) on the basis of increased mutational load. Methods We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015. Tumor mutational load, with exclusion of copy number changes, was determined for each case and compared with MMR status as determined by routine immunohistochemistry. Results Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT. Thirteen percent (n = 28) exhibited MMR-D by immunohistochemistry. Using the 341-gene assay, 100% of the 193 tumors with 150 mutations each. Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype. Among MMR-D tumors, the median number of mutations was 50 (range, 20 to 90) compared with six (range, 0 to 17) in MMR-proficient/POLE wild-type tumors (P
Source: Journal of Clinical Oncology - Category: Cancer & Oncology Authors: Tags: ASCO Guidelines, Diagnosis & Staging, Translational Oncology, Gastrointestinal, Gene Expression and Profiling, Oncogenes Gastrointestinal Cancer Source Type: research

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Muir-Torre syndrome is a rare subtype of Lynch syndrome characterized by coincidence of skin neoplasm and visceral malignancies. Here, we report a case of this rare disease, whose diagnosis of the syndrome was first suspected by the pathologist. This was a 60-yr-old woman who presented with an axillary skin nodule, which was diagnosed as basal cell carcinoma. Further inquiry revealed that she was hospitalized for evaluation of a recurrent vaginal stump endometrial carcinoma. Histologic workup and immunohistochemistry for mismatch repair proteins of both the skin and vaginal tumor suggested the possibility of Muir-Torre syn...
Source: International Journal of Gynecological Pathology - Category: Pathology Tags: Pathology of the Corpus: Case Reports Source Type: research
ConclusionThe patient presented represents the first reported case where both next generation sequencing (NGS) forBRCA LOH and MMR IHC testing of her breast cancer were performed and underscores the importance of using NGS including the reported mutational allelic frequency (MAF) and IHC use to predict the likely responsiveness to the recently approved PARP inhibitors and checkpoint inhibitor therapies (Robson et al in N Engl J Med 377:523 –533, 2017, Lemery et al in 377(15):1409–1412,, 2017), key because the gatekeeper transforming event for tumors related to inherited cance...
Source: Breast Cancer Research and Treatment - Category: Cancer & Oncology Source Type: research
io PR Abstract It is paramount to identify patients whose cancer is associated with genetic susceptibility to the disease, since their long-term management depends on it. Anatomical and molecular pathologists play a key role in the process. Indeed, their diagnosis supports or even sometimes warrants germline genetic testing. For example, a colorectal cancer with mismatch repair protein expression loss suggests Lynch syndrome, while a rare type of renal cell carcinoma with fumarate hydrate expression loss is highly evocative of hereditary leiomyomatosis and renal cell carcinoma syndrome. Similarly, the presence of ...
Source: Annales de Pathologie - Category: Pathology Authors: Tags: Ann Pathol Source Type: research
Source: Clinical Gastroenterology and Hepatology - Category: Gastroenterology Authors: Source Type: research
Conclusions Lynch syndrome should be suspected in families with familial pancreatic cancer, even in the absence of colon cancers. Specifically, our observation supports the association between the MSH6 c.2194C>T pathogenic variant and extracolonic tumours and it suggests that MSH6 pathogenic variants are associated with familial pancreatic cancer more frequently than assumed.
Source: European Journal of Gastroenterology and Hepatology - Category: Gastroenterology Tags: Original Articles: Gastroenterology Source Type: research
CONCLUSION: This study highlights the utility of this approach, which should be applicable to laboratories performing similar testing. PMID: 31530574 [PubMed - indexed for MEDLINE]
Source: Clinical Colorectal Cancer - Category: Cancer & Oncology Authors: Tags: J Clin Pathol Source Type: research
AbstractRoutine diagnostics for colorectal cancer patients suspected of having Lynch-Syndrome (LS) currently uses Next-Generation-Sequencing (NGS) of targeted regions within the DNA mismatch repair (MMR) genes. This analysis can reliably detect nucleotide alterations and copy-number variations (CNVs); however, CNV-neutral rearrangements comprising gene inversions or large intronic insertions remain undetected because their breakpoints are usually not covered. As several founder mutations exist for LS, we established PCR-based screening methods for five known rearrangements inMLH1,MSH2, orPMS2, and investigated their preval...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research
Because of increased risk of metachronous colorectal cancer (CRC), all Lynch Syndrome (LS) patients are offered a total colectomy. However, since metachronous CRC rate by MMR gene is uncertain, and total colectomy negatively impacts quality of life, it remains unclear whether segmental resection is indicated for lower penetrance MMR genes. We evaluated metachronous CRC incidence according to MMR gene in LS patients who underwent a segmental colectomy.
Source: Journal of the American College of Surgeons - Category: Surgery Authors: Tags: Southern Surgical Association Article Source Type: research
AbstractThe hallmark of Lynch syndrome (LS)-associated neoplasia is DNA mismatch repair protein (MMR) deficiency. Recent studies have demonstrated that histologically normal colonic crypts in patients with LS can exhibit deficient MMR expression. The aim of this study was to determine the feasibility of detecting MMR deficient crypts in random colonoscopic biopsies of normal mucosa in patients with and without LS. Forty-nine patients, including 33 with LS, 12 without LS, and 4 with germline MMR gene variants of uncertain significance (VUS), were prospectively and blindly evaluated by immunohistochemistry for MMR deficient ...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research
ConclusionIdentification of families with Lynch syndrome, while challenging because of variable phenotypes at diagnosis, is feasible with available molecular biological technologies and crucial to reduce mortality caused by this syndrome.
Source: Journal of Gastrointestinal Cancer - Category: Cancer & Oncology Source Type: research
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