Germline deletion of the 3′ portion of the Epithelial Cell Adhesion Molecule (EPCAM) gene located 5′ upstream of MutS Homolog 2 (MSH2) is a novel mechanism for its inactivation in Lynch syndrome. However, its contribution in Japanese Lynch syndrome patients is poorly understood. Moreover, somatic events inactivating the remaining allele of MSH2 in cancer tissue have not been elucidated in Lynch syndrome patients with such EPCAM deletions. We identified a Japanese Lynch syndrome patient with colon cancer who evidenced germline deletion of a 4130 bp fragment of EPCAM encompassing exons 8 and 9 (c.859-672_*2170del). In normal colonic mucosa, two known fusion-transcripts of EPCAM/MSH2 generated from the rearranged gene were observed and heterozygous methylation of the MSH2 gene promoter was detected. In cancer tissue, dense methylation of MSH2 was observed and MLPA analysis demonstrated somatic deletion of the remaining EPCAM allele including exon 9, indicating that somatic deletion of EPCAM is responsible for complete inactivation of MSH2.
A 39-year-old woman underwent right colectomy for type-3 transverse colon cancer, which was histologically identified as well-differentiated stage II A adenocarcinoma with a mucinous component and tumor-infiltrating lymphocytes. The patient was suspected of having Lynch syndrome(LS)since she fulfilled 2 of the revised Bethesda criteria, even though there was no family history of LS. Twelve months after colectomy, abdominal CT revealed thickening of the uterine endometrium. Histopathological examination of biopsy specimens revealed well-differentiated endometrioid carcinoma. Extended hysterectomy with bilateral oophorectomy was performed. Histological examination of the resected specimen revealed well-differentiated endometrioid carcinoma of stage I . Immunohistochemistry analysis of mismatch repair proteins demonstrated loss of MLH1/ PMS2 expression in the colon cancer, but normal expression in the uterine cancer. Genetic testing identified duplication of exons 10-15 of the MLH1 gene, leading to a definitive diagnosis of LS. The patient has not shown any evidence of recurrence or new LS-associated tumors in the 12 years since the last surgery. There is an ongoing debate regarding the pathogenesis of endometrioid cancer, and this case emphasizes the importance of surveillance for gynecological malignancies after colon cancer surgery in female LS patients.
Background/Aim: Identifying patients with DNA mismatch repair-deficient (dMMR) colorectal cancer (CRC) is vital to improve treatment and identify patients with Lynch syndrome (LS). We developed a prediction model for dMMR CRC using clinicopathologic features. Patients and Methods: We reviewed the medical records of 1,147 patients who underwent resection of stage I-IV CRC in whom universal screening for LS using immunohistochemistry for MMR proteins had performed. Univariate and multivariate logistic regression analyses were used to build a prediction model of dMMR CRC. Results: The prevalence of dMMR CRC was 5.2%. Age (≥75 years), tumor location (right-sided colon), main histologic features (poor differentiation), maximum tumor size (≥65 mm), and stage (I/II) were independent significant variables related to dMMR. We created a formula for predicting the likelihood of dMMR, and the probability ranged from 0.2% to 83%. Conclusion: dMMR CRC can be identified efficiently using clinicopathologic features obtained in daily clinical practice.
Objectives: Although some studies have evaluated the effectiveness of comprehensive genomic profiling (CGP) in solid tumors, the effectiveness of CGP in metastatic colorectal cancer (mCRC) has not been evaluated using detailed real-world long-outcome data.
Muir-Torre syndrome (MTS) is currently considered as a clinical variant of Lynch syndrome (LS). The clinical significance of the screening of patients with MTS-associated cutaneous tumors for the identification of LS has not yet been established. In addition, the prevalence and molecular characteristics of mismatch repair (MMR) protein deficiency in such tumors has scarcely been investigated in the Japanese population.Immunohistochemistry (IHC) for MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from 16 sebaceous neoplasms (SNs) resected from 13 patients and 32 keratoacanthomas (KAs) resected from 31 patients at our institution between January 2005 and March 2014. Tumors showing MMR protein loss were further subjected to genetic analysis for detecting the presence of germline and/or somatic alterations of the MMR genes to identify the precise molecular mechanisms underlying the protein loss.Among the 16 SNs resected from 13 patients, eight SNs resected from five patients (38.5%) showed loss of expression of MMR proteins (MLH1/PMS2 loss, one patient; MSH2/MSH6 loss, four patients). Genetic analyses showed a pathogenic germline MSH2 mutation in one patient, somatic hypermethylation of the MLH1 promoter region in one patient, and somatic alterations of MSH2 without detectable germline mutations of MSH2 in three patients. None of the KAs examined in the study showed any loss of MMR protein expression.The efficacy of routine screening of cutaneous neoplasms known to be associated with MTS by IHC for MMR proteins to identify LS may be fairly limited. MMR protein loss as determined by IHC in SNs is not always diagnostic of LS, and appears, in most cases, to be a result of somatic inactivation of the MMR genes.
Microsatellite instability( MSI) in colorectal carcinoma is reportedly associated with resistance to 5-fluorouracil-based chemotherapy. Moreover, colorectal cancer patients aged ≤ 50 years could potentially have Lynch syndrome. In the present study, we examined 11 colorectal cancer patients with unresectable Stage IV disease who underwent resection of the primary tumor between January 2006 and December 2012. The relationship between the MSI status and the efficacy of first- line oxaliplatin-based chemotherapy was retrospectively examined. The MSI status included MSI-H in 1 patient, MSS-L in 2 patients, and MSS in 8 patients. The MSI-H in 1 patient was associated with familial adenomatous polyposis. Following chemotherapy, among 8 MSS patients, 3 showed stable disease (SD) and 1 showed partial response (PR). Moreover 2 MSH-L patients and 1 MSI-H patient showed progressive disease (PD) after chemotherapy. However, additional data collection is required to determine the effect of oxaliplatin-based chemotherapy for MSS-H or MSS-L colorectal patients aged ≤ 59 years.
The patient was a 65-year-old man without any noteworthy medical history. A colonoscopy conducted after a positive fecal occult blood test revealed approximately 100 polyps in the large intestine. A biopsy of some these polyps revealed serrated and hyperplastic polyps, which were histologically determined to be well-differentiated adenocarcinoma. Based on these findings, a diagnosis of serrated polyposis syndrome (SPS) was made, and the patient underwent laparoscopic pancolectomy/ileoproctostomy. Histopathological analysis revealed a total of 91 lesions, out of which 15 were ≥10 mm. A 30 mm lesion in the ascending colon was a well-differentiated adenocarcinoma, stage Ⅰ colon cancer (T1a [sm], ly0, v0, N0, and M0). No germline mutations were found on genetic testing of the adenomatous polyposis coli (APC), mutY homolog (MUTYH), mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and postmeiotic segregation increased 2 (PMS2) genes. No loss of MLH1 protein expression or expression of mutated B-Raf (BRAF) V600E protein was observed in the cancer regions after immunostaining. This case is important because not only is the condition rare but also because it showed that the serrated pathway may not necessarily be the mechanism by which serrated lesions become cancerous in patients with SPS.
Small bowel carcinoma is a rare tumor, for which a standardized chemotherapy regimen has not yet been established. Further, this tumor may belong to the group of Lynch syndrome-associated tumors, which are resistant to 5-fluorouracil (5-FU) -based chemotherapy. We investigated mismatch repair protein expression and K-ras gene mutation status in 8 patients with aggressive small bowel carcinoma and determined the chemotherapy regimen used in these patients. Immunohistochemical staining indicated normal mismatch repair protein expression in all surgical specimens. Of 8 patients, 4( 50%) had K-ras codon 12 mutations. Because small bowel carcinoma is not significantly associated with Lynch syndrome, 5-FU-based chemotherapy would be appropriate for the treatment of these patients. The prevalence of K-ras codon 12 mutations was relatively similar to that in patients with sporadic colorectal carcinoma, and the usefulness of anti- epidermal growth factor receptor (EGFR) antibody for the treatment of small bowel carcinoma should be evaluated in the future.
This retrospective study was undertaken to examine the usefulness of Köhne's index(KI) for predicting the efficacy of first-line oxaliplatin-based chemotherapy for unresectable liver metastases of colorectal cancer.The subjects were 84 patients with unresectable liver metastases of colorectal cancer in whom first-line oxaliplatin- based chemotherapy was administered. The outcome of treatment was analyzed in relation to the KI.The patients were classified into 3 groups: high risk group (n=12), intermediate risk group (n=20), and low risk group (n=52). There were no significant differences between the groups with regard to response rate, disease control rate, disease-free survival, overall survival, and the rate of conversion to hepatic metastatectomy.Our results suggest that KI might not be useful for predicting the efficacy of first-line oxaliplatin-based chemotherapy for unresectable liver metastases of colorectal cancer.
