Rate Of Microsatellite Instability Research Articles

The insights of mutations of gynecological oncology by liquid biopsy for Chinese patients.

e17501 Background: Liquid biopsy drew dramatic attention in the field of cancer research because of its attribution of nontraumatic, easy to obtain, providing overall state of tumor, allowing for real-time monitoring and so on. However, the transformation from research to application of liquid biopsy technique in clinical gynecological oncology management require more evidence and further investigation. Methods: Blood samples of 104 patients were collected, of whom 33 were diagnosed as cervical cancer, 20 were diagnosed as endometrial cancer, and 51 were diagnosed as ovarian cancer. cfDNA were extracted from blood and examined by next-generation sequencing technique with Haplox HapOnco panel. cfDNA mutations were analyzed and compared with genomic mutations in tumor tissues in publications. Results: In cfDNA, there were 120 genes mutated in cervical cancer patients, 150 genes mutated in endometrial cancer patients, and 58 genes mutated in ovarian cancer patients. Detecting by cfDNA, the average number of mutations was 6 (4.1 to 7.9, 95% CI) for each cervical cancer patient, 8.1 (2.1 to 14.1, 95% CI) for each endometrial cancer patient, and 5.1 (3.7 to 6.5, 95% CI) for each ovarian cancer patient. As the mutations in cfDNA compared with those in tumor tissues, the results revealed that there was no significant difference in mutation rate for 94.2% genes in blood and tumor tissues for cervical cancer patients, 93.3% for endometrial cancer patients, and 98.3% for ovarian cancer patients. Besides, there were no significant differences in microsatellite instability rates in blood and tumor tissues for cervical cancer patients and endometrial cancer patients. Conclusions: Most mutated genes in tumor tissues were detected in blood for gynecological oncology patients. The mutation rate for most genes and microsatellite instability rate had no significant difference in blood and tumor tissues, which suggested that liquid biopsy using cfDNA is helpful in gynecological oncology management.

Molecular and phenotypic profiling of colorectal cancer patients in West Africa reveals biological insights

Understanding the molecular and phenotypic profile of colorectal cancer (CRC) in West Africa is vital to addressing the regions rising burden of disease. Tissue from unselected Nigerian patients was analyzed with a multigene, next-generation sequencing assay. The rate of microsatellite instability is significantly higher among Nigerian CRC patients (28.1%) than patients from The Cancer Genome Atlas (TCGA, 14.2%) and Memorial Sloan Kettering Cancer Center (MSKCC, 8.5%, P < 0.001). In microsatellite-stable cases, tumors from Nigerian patients are less likely to have APC mutations (39.1% vs. 76.0% MSKCC P < 0.001) and WNT pathway alterations (47.8% vs. 81.9% MSKCC, P < 0.001); whereas RAS pathway alteration is more prevalent (76.1% vs. 59.6%, P = 0.03). Nigerian CRC patients are also younger and more likely to present with rectal disease (50.8% vs. 33.7% MSKCC, P < 0.001). The findings suggest a unique biology of CRC in Nigeria, which emphasizes the need for regional data to guide diagnostic and treatment approaches for patients in West Africa.

Abstract IA35: Novel biological insights into colorectal cancer from West Africa

Abstract The burden of colorectal cancer (CRC) is increasing in West Africa. Understanding the molecular and clinicopathologic profile of the region’s CRC patients is vital to optimizing early detection and therapeutic regimens. Clinicopathologic data from consecutive patients from a multicenter, prospectively maintained Nigerian CRC database were compared to a contemporary cohort from Memorial Sloan Kettering Cancer Center (MSKCC). Fresh-frozen tissue from Nigerian patients was analyzed with a multigene, next-generation sequencing assay, along with immunohistochemistry and methylation analyses; data were compared to molecular data from MSKCC and The Cancer Genome Atlas (TCGA) cohorts. Adult patients with histologically confirmed colorectal adenocarcinoma enrolled in a Nigerian CRC database from April 2013-November 2018 were included. All adult patients with colorectal adenocarcinoma diagnosed from January-June 2013 were included in the MSKCC cohort. Somatic and germline next-generation sequencing of cancer-associated genes, immunohistochemistry, and methylation analyses were performed. The primary outcomes were microsatellite instability status, somatic and germline mutation frequency, and overall survival. The median age at diagnosis was 55.8 years in the Nigerian cohort (n=380) and 60.0 years in the MSKCC cohort (n=458) (p&amp;lt;0.001). The rate of microsatellite instability was 28.1% in the Nigerian cohort (18/64), compared to 14.2% and 8.5% in the TCGA (65/459) and MSKCC (97/1145) cohorts, respectively (p&amp;lt;0.001). In microsatellite-stable cases, tumors from Nigerian patients were less likely to have APC mutations (39.1% vs. 76.0% p&amp;lt;0.001) and WNT pathway alterations (47.8% vs. 81.9%, p&amp;lt;0.001), and more likely to have RAS pathway alterations (76.1% vs. 59.6%, p=0.03) compared to MSKCC patients. Overall survival was significantly longer for MSKCC vs. Nigerian patients (not reached vs. 12 months, p&amp;lt;0.001). The biology of CRC in Nigeria appears to be distinct from that in high-income countries, emphasizing the need for regional data to guide diagnostic and treatment approaches for patients in West Africa. Citation Format: Olusegun I. Alatise, Gregory C. Knapp, Avinash Sharma, Walid K. Chatila, Olalekan Olasehinde, Adeleye D. Omisore, Aba Katung, Samuel A. Olatoke, T.Peter Kingham. Novel biological insights into colorectal cancer from West Africa [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA35.

Microsatellite instability status does not predict total lymph node or negative lymph node retrieval in stage III colon cancer

The relationship between higher total lymph node resection number in colorectal cancer resection specimens and improved overall survival is well known. Recent studies describe an association between a high rate of microsatellite instability and a high total lymph node count in colorectal cancer. Higher lymph node retrieval may potentially explain the improved survival seen in cancers with microsatellite instability. We investigate whether these associations can be validated in a cohort of American Joint Committee on Cancer stage III colon cancers. Medical records from 200 cases of stage III colon cancer resection specimens were reviewed, and sufficient tissue was available for 168. Expression of DNA mismatch repair proteins was determined by immunohistochemistry, and microsatellite status, by polymerase chain reaction. The mean total lymph node count in cases with microsatellite instability versus microsatellite stable tumors (15.9 versus 16.9; P = .664) and the mean number of negative lymph nodes in each respective category (12.2 versus 13.6; P = .522) were not significantly different. There was no difference between microsatellite stable cases and cases with microsatellite instability when total lymph node counts (P = .953) or negative lymph node counts (P = .381) were analyzed with respect to percentage of cases above and below the medians. This cohort of stage III colon cancers does not support a significant relationship between microsatellite status and a higher retrieval of total or negative lymph nodes. Although microsatellite instability is associated with improved overall survival in our cohort (P = .026), the reason for this does not appear to be related to higher numbers of retrieved lymph nodes.

Selection of Endometrial Carcinomas for DNA Mismatch Repair Protein Immunohistochemistry Using Patient Age and Tumor Morphology Enhances Detection of Mismatch Repair Abnormalities

Women with hereditary nonpolyposis colorectal cancer (HNPCC) have a high risk for endometrial cancer (EC) and frequently present with a gynecologic cancer as their first or sentinel malignancy. Identification of these patients is important given their personal and family risk for synchronous and metachronous tumors. The revised Bethesda Guidelines provide screening criteria for HNPCC in colorectal cancers. However, there are currently no such screening recommendations for women with endometrial carcinoma. We applied some of the colorectal cancer screening criteria, including age and tumor morphology, to endometrial endometrioid carcinoma. The purpose of this study was to describe patient and tumor characteristics and to assess the ability of these criteria to enhance detection of mismatch repair (MMR) deficiency, and hence HNPCC in EC. Immunohistochemistry (IHC) for DNA mismatch repair (IHC-MMR) proteins was performed in a defined subset of patients with EC. This included women younger than 50 years of age and women >or=50 years whose tumors showed morphologic features suggestive of MMR deficiency (TM-MMR). The extent of IHC-MMR in the older patient group was compared with that in a comparison group of EC >or=50 years that was previously analyzed for microsatellite instability status. Seventy-one patients met the selection criteria for IHC testing; 32 (45%) showed abnormal results. The rate of IHC abnormality in the younger group was approximately 30% with a nearly equal distribution of MLH1/PMS2 and MSH2/MSH6 abnormalities. In the older age group, TM-MMR triggered IHC analysis in 31 of 34 cases. Of these, 18 cases showed loss of IHC-MMR (58% of cases), 7 with loss of MSH2/MSH6. In contrast, the rate of microsatellite instability in the comparison group was only 21%. The IHC abnormal group showed more frequent tumor infiltrating lymphocytes, dedifferentiated EC, more tumors centered in the lower uterine segment, and more frequent synchronous clear cell carcinomas of the ovary than tumors with a normal immunophenotype. Although many of the patients with loss of IHC-MMR showed personal and/or family history (13 of 32) of HNPCC-associated tumors, most did not. Tumor morphology (TM-MMR) along with IHC-MMR enhances the detection of EC patients at risk of HNPCC.

Molecular genetic alterations in endometrioid carcinomas of the ovary: Similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas*1

Molecular genetic alterations in endometrioid carcinomas of the ovary: Similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas*1

Hypermethylation of the hMLH1 promoter with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly

To clarify the significance of hMLH1 promoter hypermethylation in the development of medullary-type poorly differentiated colorectal adenocarcinoma, we studied the status of promoter methylation and hMLH1 expression in 23 medullary-type and 12 pleomorphic-type carcinomas, as well as the pathology and microsatellite status. In medullary-type carcinomas, the percentages of cases with promoter methylation (83%) and an absence of hMLH1 expression (91%) were significantly higher than in pleomorphic-type carcinomas (14 and 17%), respectively. The rate of microsatellite instability in the medullary type was significantly higher than that of the pleomorphic type (87 vs 40%, P<0.01). Compared with pleomorphic-type carcinomas, medullary-type carcinomas were significantly associated with hMLH1 promoter methylation, absent expression of hMLH1 protein, microsatellite instability, as well as a proximal location, a Crohn's-like lymphoid reaction, a low incidence of lymph node metastasis, and a favorable outcome. Medullary-type carcinomas accumulated with advancing age, especially in the female. These results indicated that hMLH1 hypermethylation, concurrent with a lack of its protein expression, may play an important role in the development of medullary-type poorly differentiated colorectal adenocarcinomas in the elderly.

Rate of microsatellite instability in young patients with adenomas: assessment of bethesda guidelines to detect HNPCC

Rate of microsatellite instability in young patients with adenomas: assessment of bethesda guidelines to detect HNPCC

High-density allelotype of the commonly studied gastric cancer cell lines.

Gastric cancer is one of the leading causes of death from cancer throughout the world, and studies to elucidate the genetic defects found in this type of cancer are growing in number. Increasingly sophisticated techniques and the sequencing of the human genome have had an impact on the scope of such studies. While the use of tumor specimens remains popular, more emphasis is being placed on cell lines as model systems where specific data can be directly combined with results from other studies. This article describes a genetic survey of the most widely used gastric adenocarcinoma cell lines. The allelotype at 351 polymorphic loci in 14 cell lines was obtained, and the results from the 4,900 polymerase chain reactions are displayed. In addition to confirming loss of heterozygosity on chromosome arms 6p, 7q, 17p, and 18, additional deletions on arm 5p and the pericentromeric regions of chromosomes 1 and 10 were detected. Areas that might contain homozygous deletions or amplifications also were mapped. The rate of microsatellite instability was quantified and shown to vary greatly among the different cell lines. Most important, this study serves as a genetic scaffold for the integration of past and future studies on the nature of the genetic defects in gastric cancer.

Microsatellite instability and aneuploidy rate in young colorectal-cancer patients do not differ significantly from those in older patients.

DNA and chromosomal instabilities are thought to promote colorectal carcinogenesis. Mismatch repair (MMR) deficiency affects DNA-sequence integrity, resulting in microsatellite instability (MI). Tumor aneuploidy (AN) has been shown to reflect underlying chromosomal instability (CI). This study aimed at assessing the MI and AN rate of Singapore's colorectal-cancer (CRC) patients, who are predominantly Chinese, in association with age group, tumor site, Dukes' staging and gender. In contrast to a Caucasian series, the MI rate for our younger patients aged 40 or less without family history (23%) is not significantly different from that for older, sporadic patients (13%) aged 60 or more, suggesting that population screening for germline MMR mutations is unlikely to be cost-effective. Our MI-positive patients also show no significant differences from the MI-negative patients with respect to tumor site, staging, ploidy status and gender. This implies that the local MI-positive individuals may have a different profile from that of the Caucasians, indicating the possibility of underlying genetic differences. AN is also not significantly more prevalent in younger patients. In addition, a significant 21% of our patients (p < 0.00005) show no evidence of either the MI or CI pathways, implying that there is at least a third pathway driving colorectal carcinogenesis, involving neither genes that maintain DNA sequence stability nor genes that cause gross chromosomal segregation defects.