A case report of a patient with first phenotype of papillary thyroid carcinoma and heterochronous multiprimary tumor harboring germline MUTYH Arg19*/Gly286Glu mutations.

MUTYH-associated polyposis (MAP) is an autosomal recessively inherited disease with multiple system tumors mainly in alimentary system. Tumor occurrence of MAP patients is highly heterogeneous in space and time. MAP is associated with germline biallelic mutations in MUTYH. The targeted next­generation sequencing technology and Sanger sequencing are the important methods to screen MUTYH mutations now. Herein, we identified a patient with heterochronous multiprimary tumor carring MUYTH Arg19*/Gly286Glu compound heterozygous mutations. The patient in this case had a first phenotype of thyroid cancer at age 44, which earlier 2 years than the alimentary system cancers. In conclusion, our case report creases the in-depth understanding of the MAP heterogeneous phenotype and further reminds recommendations for improvement of health management and genetic counseling, special treatment plans.

Identification of the HT-29 cell line as a model for investigating MCT1 transporters in sigmoid colon adenocarcinoma.

MCT1 transporters play a crucial role in the symbiotic relationship between humans and their colonic microbiome by facilitating the transport of bacteria-derived short chain fatty acids. Expression of colonic MCT1 transporters, localized in surface epithelial cells, is regulated by luminal butyrate levels. However, MCT1 also transports lactate and can be used by cancer cells to facilitate anaerobic glycolysis. Using immunolocalization techniques, this study investigated whether changes in MCT1 during cancer varied between different colonic regions. Whilst MCT1 abundance did not significantly change in transverse colon adenocarcinoma (P = 0.363, N = 6, paired T-Test), there was an increase in MCT1 in sigmoid colon adenocarcinoma (P = 0.010, N = 21, paired T-test). Using RT-PCR and western blotting, three human intestinal cell lines were tested for their suitability as a MCT1 cancer cell model. Experiments with Caco-2 cells confirmed that they modelled normal cells, with MCT1 only expressed after exposure to butyrate. In contrast, MCT1 was expressed in the absence of butyrate in both HCT-8 and HT-29 cell lines, with consistently high levels of MCT1 protein being present in HT-29 cells. Furthermore, butyrate treatment of HT-29 cells significantly decreased both MCT1 protein abundance (P < 0.001, N = 4, unpaired T-test) and glycosylation of its' chaperone protein, CD147 (P < 0.001, N = 4, unpaired T-test). These data suggest that (i) MCT1 transporter abundance increases in sigmoid colon adenocarcinoma, and (ii) HT-29 cells are an appropriate cell model with which to investigate MCT1 function in this disease.

Microsatellite Instability in Greek Colorectal Carcinoma Patients: Clinicopathological and Molecular Correlations.

BACKGROUND/AIM: In the present retrospective study, we assessed the molecular profile and clinicopathological correlations of Greek colorectal carcinoma (CRC) patients. PATIENTS AND METHODS: Data from 157 CRC patients were collected. High Resolution Melting Analysis and Pyrosequencing/Sanger sequencing were applied to identify KRAS, BRAF, NRAS mutations and microsatellite instability (MSI) status. Immunohistochemistry was performed to characterize the associated Mismatch Repair Protein loss. Statistical calculations were performed using the statistical package SPSS v21.0. RESULTS: KRAS mutations were detected in 39.3% of cases, BRAF in 10.9% and NRAS in 4.9%. MSI status was recognized in 11.5% of CRC patients and was associated with right colon tumors. MSI phenotype was inversely correlated with stage, N status and KRAS mutations and positively correlated with BRAF mutations. CONCLUSION: MSI positive CRCs in the Greek population are more often right-sided, free of metastasis, KRAS wild type and BRAF mutated. Providing more detailed clinicopathological and molecular data for specific populations will enable better clinical management and individualized therapy in the future.

Identification of a novel PRR15L-RSPO2 fusion transcript in a sigmoid colon cancer derived from superficially serrated adenoma.

Superficially serrated adenoma (SuSA) is a recently proposed subtype of colorectal serrated lesion. We here report a sigmoid colon cancer derived from SuSA, which exhibited aggressive clinical behavior. Endoscopically, the tumor appeared as a superficial elevated lesion with a large nodule. Histological examination of the surgically resected material showed tubular adenocarcinoma associated with SuSA. Although tumor invasion was limited to the submucosal layer, lymph node and extranodal metastases were detected. The patient subsequently developed peritoneal metastases and died 15 months after surgery. Molecular analyses identified a KRAS mutation and a novel PRR15L-RSPO2 fusion, which retains the entire coding region of RSPO2, in both SuSA and adenocarcinoma components. The present study demonstrates the malignant potential of SuSA and expands the spectrum of RSPO fusions in colorectal neoplasms.

Clinical and Molecular Features of Post-Colonoscopy Colorectal Cancers.

BACKGROUND & AIMS: Post-colonoscopy colorectal cancers (PCCRCs) may arise from missed lesions or due to molecular features of tumors that allow them to grow rapidly. We aimed to compare clinical, pathology, and molecular features of PCCRCs (those detected within 6-60 months of colonoscopy) and detected CRCs (those detected within 6 months of a colonoscopy). METHODS: Within a population-based cross-sectional study of incident CRC cases in Utah (from 1995 through 2009), we identified PCCRCs (those cancers that developed within 5 years of a colonoscopy) and matched the patients by age, sex, and hospital site to patients with detected CRC. Archived specimens were retrieved and tested for microsatellite instability (MSI), CpG island methylation, and mutations in KRAS and BRAF. There were 2659 cases of CRC diagnosed within the study window; 6% of these (n = 159) were defined as PCCRCs; 84 of these cases had tissue available and were matched to 84 subjects with detected CRC. RESULTS: Higher proportions of PCCRCs than detected CRCs formed in the proximal colon (64% vs 44%; P = .016) and were of an early stage (86% vs 69%; P = .040). MSI was observed in 32% of PCCRCs compared with 13% of detected CRCs (P = .005). The other molecular features were found in similar proportions of PCCRCs and detected CRCs. In a multivariable logistic regression, MSI (odds ratio, 4.20; 95% CI, 1.58-11.14) was associated with PCCRC. There was no difference in 5-year survival between patients with PCCRCs vs detected CRCs. CONCLUSION: In this population-based cross-sectional study of incident CRC cases in Utah, we found PCCRCs to be more likely to arise in the proximal colon and demonstrate MSI, so PCCRCs and detected CRC appear to have different features or processes of tumorigenesis. Additional studies are needed to determine if post-colonoscopy cancers arise through a specific genetic pathway.

Metachronous metastasis to inguinal lymph nodes from sigmoid colon adenocarcinoma with abdominal wall metastasis: a case report.

BACKGROUND: Inguinal lymph node metastasis from rectum is uncommon but well-known occurrence, whereas that from colon adenocarcinoma is extremely rare. Inguinal lymph node metastasis from colon adenocarcinoma has only been reported in previous cases involving primary tumor invasion of the abdominal wall, or in those involving colon cancer metastasis to external iliac lymph nodes. We describe a case of inguinal lymph node metastasis from colon cancer without primary tumor invasion to the abdominal wall. CASE PRESENTATION: A 42-year-old female, who had undergone twice cesarean sections before, underwent open sigmoidectomy for sigmoid colon adenocarcinoma and received 12 cycles of FOLFOX regimen as adjuvant chemotherapy. Two years after sigmoidectomy, a follow-up CT scan revealed enlarged inguinal lymph nodes as well as growth of enhanced mass lesions on the abdominal wall at site of the cesarean section scar. Biopsy of both lesions revealed well-differentiated adenocarcinoma, and immunohistochemistry demonstrated positive expression of CDX2, substantiating its gastrointestinal origin. We therefore performed dissection of left inguinal lymph nodes and mass lesion of the abdominal wall. The patient died 51 months after lymph node dissection. CONCLUSIONS: This is the first reported case of inguinal lymph node metastasis from colon cancer without invasion of the primary tumor to the abdominal wall or without involvement of the external iliac lymph nodes, suggesting that the pathway of inguinal metastasis originated from the abdominal wall metastasis. When inguinal lymph node metastasis from colon cancer is suspected, if an R0 resection was possible, inguinal lymph node dissection may be a potentially effective treatment.

Sigmoid Colon Adenocarcinoma with Isolated Loss of PMS2 Presenting in a Patient with Synchronous Prostate Cancer with Intact MMR: Diagnosis and Analysis of the Family Pedigree.

Lynch syndrome (LS) patients with isolated PMS2 loss in the colon cancer, while intact MMR in the prostate cancer, are exceedingly rare. Herein, we report such a case. A 71-year-old male was found to have increased serum PSA (10 ng/ml) after treatment for his urinary tract infection. Prostate biopsies showed foci of prostate cancer with Gleason score 7 (3+4) (grade grope 2) involving 10% of two cores. Through work up for treatment of the prostate cancer, he was found to have focal thickening of his sigmoid colon with adjacent lymphadenopathy in CT scans. Colon biopsy showed a tubular adenoma with high-grade dysplasia and deep invasive carcinoma could not be excluded. A low anterior resection of the rectosigmoid colon was performed and a sigmoid colon adenocarcinoma (pT2N1b, AJCC 8th edition) was confirmed. Immunostaining showed that the colon cancer was positive for CDX2, SATB2, had a loss of PMS2 and intact expression of MLH1, MSH2 and MSH6, negative for AMACR, while the prostate cancer was positive for AMACR, had intact expression of PMS2, MLH1, MSH2 and MSH6, and negative for CDX2 and SATB2. MSI-H phenotype and PMS2 mutation in the colon cancer were confirmed by microsatellite instability (MSI) PCR and next-generation sequencing (NGS), respectively. Through genetic counseling and analysis of the family pedigree, LS was confirmed with colon cancer present in multiple maternal family members and his brother also had metachronous colon and prostate cancers. To the best of our knowledge, this is the first documented case of synchronous colon and prostate cancers, with isolated PMS2 loss present in the colon cancer while intact DNA mismatch repair (MMR) protein expressions present in the prostate cancer, in the English literature. The pathogenesis, diagnosis and prognosis of this entity are discussed.

Contiguous gene deletion of chromosome 2p16.3-p21 as a cause of Lynch syndrome.

Lynch syndrome is an autosomal dominant condition caused by pathogenic mutations in the DNA mismatch repair (MMR) genes. Although commonly associated with clinical features such as intellectual disability and congenital anomalies, contiguous gene deletions may also result in cancer predisposition syndromes. We report on a 52-year-old male with Lynch syndrome caused by deletion of chromosome 2p16.3-p21. The patient had intellectual disability and presented with a prostatic adenocarcinoma with an incidentally identified synchronous sigmoid adenocarcinoma that exhibited deficient MMR with an absence of MSH2 and MSH6 protein expression. Family history was unrevealing. Physical exam revealed short stature, brachycephaly with a narrow forehead and short philtrum, brachydactyly of the hands, palmar transverse crease, broad and small feet with hyperpigmentation of the soles. The patient underwent total colectomy with ileorectal anastomosis for a pT3N1 sigmoid adenocarcinoma. Germline genetic testing of the MSH2, MSH6, and EPCAM genes revealed full gene deletions. SNP-array based DNA copy number analysis identified a deletion of 4.8 Mb at 2p16.3-p21. In addition to the three Lynch syndrome associated genes, the deleted chromosomal section encompassed genes including NRXN1, CRIPT, CALM2, FBXO11, LHCGR, MCFD2, TTC7A, EPAS1, PRKCE, and 15 others. Contiguous gene deletions have been described in other inherited cancer predisposition syndromes, such as Familial Adenomatous Polyposis. Our report and review of the literature suggests that contiguous gene deletion within the 2p16-p21 chromosomal region is a rare cause of Lynch syndrome, but presents with distinct phenotypic features, highlighting the need for recognition and awareness of this syndromic entity.

Fibromatosis of the Sigmoid Colon With CTNNB1 (ß-Catenin) Gene Mutation, Arising at the Site of Ileocolic Anastomosis for Resection of Gastrointestinal Stromal Tumor.

We describe a case of intra-abdominal fibromatosis, which occurred in a 44-year-old woman who had a previous history of gastrointestinal stromal tumor (GIST) of the sigmoid mesocolon, which was treated with imatinib and resection. A mass was detected at the site of ileocolic anastomosis of the previous small bowel resection and sigmoid colectomy, nearly 3 years later. Clinically, this was suspected to represent recurrent GIST and was excised, but histology and mutational analysis showed desmoid-type fibromatosis with a mutation in codon 41 of exon 3 of the CTNNB1 (ß-catenin) gene. The occurrence of fibromatosis at the site of excision of GIST is very rare, but its recognition is important as the treatment of the two neoplasms differs significantly. As imaging cannot reliably distinguish between these 2 entities, histological diagnosis is crucial for correct clinical management.

[A Family Affected by Lynch Syndrome Caused by MSH6 Germline Mutation].

The clinical features of Lynch syndrome caused by MSH6 are not fully understood since very few cases have been described in Japan. We report 2 cases of Lynch syndrome with germline mutation of MSH6 in a family. Case 1: A 47-year-old man was referred to our department due to positive fecal occult blood test. He had family history of endometrial cancer and gastric cancer (mother), and bladder cancer (father). We performed sigmoidectomy for sigmoid cancer. The pathological findings revealed mucosal cancer (pTis, pN0, H0, P0, pStage 0). Since the patient met the revised Bethesda guidelines, we performed microsatellite instability (MSI) testing and immunohistochemistry for mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) as screening for Lynch syndrome. MSI-high and loss of MSH6 were found. Based on these results, genetic testing of MSH6 revealed a frame-shift mutation in codon 604 (c. 1806-1809delAAG/p. Glu604LeufsX5). Case 2: The patient was a younger brother of case 1. The same mutation was detected in the MSH6 gene.

Molecular and immunohistochemical profile of a basaloid (cloacogenic) carcinoma of the sigmoid colon: possible predictive value for clinical outcomes.

A 61-year-old woman was hospitalized with a 5-week history of abdominal discomfort, change in bowel habits, and weight loss. Colonoscopy showed a protruded tumor of the sigmoid colon first diagnosed as undifferentiated carcinoma. Surgical resection of the sigmoid colon was performed. Histological examination of the surgical specimen showed a proliferation of basaloid cells arranged in tumor clusters with central comedonecrosis and peripheral palisading of the nuclei. The tumor invaded the subserosa and presented liver metastasis without lymph node metastases. The tumor cells were marked by keratin AE1/AE3, keratin 5/6, epithelial membrane antigen, bcl-2, vascular endothelial growth factor, CD105, neuron-specific enolase, MLH-1, MSH-2, and p53, and were negative for keratin 7/20, chromogranin, synaptophysin, carcinoembryonic antigen, p63, c-KIT, and maspin. A high p53 nuclear index was also detected. On the basis of these characteristics and molecular examinations, the final diagnosis was microsatellite stable/human papilloma virus-negative/K-ras mutated/BRAF wild-type basaloid carcinoma (BC). Only seven BCs of the colon were reported in the literature, this being the eighth one and the first case that reports new molecular findings about microsatellite instability, K-ras/BRAF mutations, angiogenesis, and maspin expression in BC, with direct involvement in targeted therapy.

A case of diffuse infiltrating gastrointestinal stromal tumor of sigmoid colon with perforation.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and typically present as discrete well-circumscribed but non-encapsulated tumor masses. In this report, we describe a case of colonic perforation caused by an unusual form of GIST. A 72-year-old Japanese woman presented to the emergency department with acute abdominal pain. Under the provisional diagnosis of sigmoid colon perforation, a laparoscopic sigmoidectomy was performed. Although the tumor mass was undetectable during the preoperative examination, a spindle cell lesion with a diffuse longitudinal growth pattern replacing the muscularis propria was revealed by microscopic examination. The spindle cell lesion was exposed at the perforation, suggesting a causal relationship between the lesion and the perforation. The spindle cell lesion was KIT-positive and had a mutation in the C-KIT gene at exon 11. We diagnosed it as diffuse infiltrating GIST. We consider that the lesion would be a cause of the colonic perforation, and emphasize the importance of accurate diagnosis of the lesion by histological, immunohistochemical and genetic examinations.

Allelic imbalance at an 8q24 oncogenic SNP is involved in activating MYC in human colorectal cancer.

BACKGROUND: The rs6983267 at 8q24.21 has been established as a significant cancer-related single nucleotide polymorphism (SNP). The risk allele showed similarity to the binding site of transcription factor TCF4/LEF1 that activates transcription of MYC. However, little is known about the role of this SNP in increasing MYC activity in colorectal cancers (CRCs). METHODS: The genotypes of rs6983267 in peripheral blood and primary cancers, MYC activity and copy number (CN) alteration were examined in 107 CRCs. Next, we plotted the number of cancers cell lines exhibiting specific G/T genotypes in 746 cancer cell lines of the Sanger Institute database. Then we validated the relationship between the 8q24 SNP status and clinicopathologic parameters in 68 CRCs with loss of heterozygosity (LOH). RESULTS: The MYC module activity was activated by either transcription in the risk allele (G) or by amplification in the non-risk allele (T). Then, we confirmed that the CN amplification dominantly occurred in the non-risk allele, whereas CN neutral LOH, which indicated uniparental disomy (UPD) was more frequently observed for the risk allele. Finally, we confirmed that risk allele dominant cases, either by amplification or by UPD, indicated a more malignant clinical phenotype than non-risk allele dominant cases. CONCLUSIONS: The development of CRC requires MYC activation through retention of the risk allele, or amplification of the non-risk allele at the oncogenic SNP in the site of primary tumor.

[A case of locally advanced sigmoid colon cancer curatively resected after neoadjuvant chemotherapy with FOLFIRI plus panitumumab].

A 72-year-old woman having abdominal pain and high fever was diagnosed with KRAS wild-type sigmoid colon cancer, invading the urinary bladder and uterus with a pelvic abscess. Considering the difficulty of curative resection, we first performed sigmoid colostomy and abscess drainage. Remarkable tumor regression was indicated by CT and colonoscopy after 1 course of FOLFIRI and 5 courses of FOLFIRI+panitumumab. Following an additional 2 courses of panitumumab, sigmoidectomy and partialcystectomy were performed. Six courses of FOLFIRI+panitumumab were administered postoperatively and no recurrence has been observed for 7 months. FOLFIRI+panitumumab may be an effective preoperative chemotherapy for patients with KRAS wild-type locally advanced colon cancer.

Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/ß-catenin signalling thresholds for tumourigenesis.

Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/ß-catenin signalling levels 'just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/ß-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers.

[Brainstem metastasis from a prostate adenocarcinoma in the context of Muir-Torre syndrome]. / Metástasis de un adenocarcinoma prostático en tronco cerebral en el contexto de un síndrome de Muir-Torre.

INTRODUCTION: Muir-Torre syndrome is a genetic disease characterised by the association of sebaceous neoplasms with visceral neoplasms, mainly colorectal cancer and secondly urogenital tumours. Metastases from prostate tumours without systemic disease are rare in the brain and exceptional in the brainstem. CASE REPORT: We present a 48-year old male, with a single brainstem metastasis from a prostate adenocarcinoma, who had previously been diagnosed with Muir-Torre syndrome. Diagnostic stereotactic biopsy was performed. CONCLUSION: Single metastasis from a prostate adenocarcinoma in the brainstem without systemic disease is exceptional. Due to the different diagnostic possibilities, biopsy should be performed in order to obtain a diagnosis, especially in the context of Muir-Torre syndrome.