Xavier Matias-Guiu

Background:  Muir‐Torre syndrome (MTS) is characterized by the co‐existence of sebaceous gland tumors of the skin and internal malignancies. Currently, MTS is regarded as a variant of the hereditary non‐polyposis colon cancer syndrome (HNPCC). Both MTS and HNPCC are secondary to germline mutations in DNA mismatch repair genes (mainly MSH‐2 and MLH‐1).Methods:  Cutaneous (eight sebaceous adenomas, one sebaceous carcinoma and one keratoacanthoma) and internal tumors (four colonic adenocarcinomas, two endometrial carcinomas, two transitional cell carcinomas of renal pelvis and ureter, one adenocarcinoma of the small bowel, one ovarian carcinoma and one colonic tubular adenoma) were obtained from six patients with MTS and were subjected to microsatellite instability (MI) analysis, and to immunostaining for MLH‐1 and MSH‐2. MI was assessed by evaluating three (CA)n dinucleotide repeats (D2S123, D5S346, D17S250) and the mononucleotide tracts BAT 26 and BAT 25.Results:  All cutaneous and internal tumors exhibited MI. An immunohistochemical concordance between all tumors within each single patient was obtained in five cases. In these five patients all tumors exhibited a lack of MSH‐2 staining, consistent with a germline abnormality in this gene. In the one remaining case, the immunohistochemical staining in the sebaceous adenoma was negative for MLH‐1 and positive for MSH‐2, consistent with a germline alteration in MLH‐1. However, the colonic adenocarcinoma in that patient showed positivity for MSH‐2 and an equivocal positivity for MLH‐1.Conclusions: The results confirm that tumors from patients with MTS exhibit MI. Moreover, immunostaining for MLH‐1 and MSH‐2 may be useful to identify the most probable gene responsible for the disease in each family.

BACKGROUND Microsatellite instability (MI) is frequent in endometrial carcinomas (ECs), but its occurrence in ovarian tumors is uncertain. Microsatellite instability positive ECs frequently are associated with frameshift mutations in coding mononucleotide tracts in IGFIIR, BAX, hMSH6, and hMSH3. METHODS DNA from 52 consecutive patients with ovarian tumors (10 benign, 7 borderline, and 35 malignant) was obtained from neoplastic and normal tissue. After preliminary results, the series was expanded by including 41 additional, previously selected, endometrioid and clear cell carcinomas. Microsatellite instability analysis was assessed by evaluating three (CA)n dinucleotide repeats (D2S123, D5S346, D17S250) and two mononucleotide tracts (BAT 25 and BAT 26). Frameshift mutations at coding mononucleotide repeats (IGFIIR, TGFβII, BAX, hMSH6, and hMSH3) were investigated by single‐strand conformation polymorphism analysis and DNA sequencing. MLH‐1 methylation was assessed by methylation specific PCR. RESULTS Microsatellite instability was identified in only 2 of the 52 (3.8%) tumors of the initial series (1 endometrioid and 1 clear cell carcinoma). After expanding the initial series of 15 endometrioid and clear cell carcinomas with 41 additional endometrioid and clear cell carcinomas, MI was found in 7 of the total series of 56 endometrioid and clear cell carcinomas (12.5%). Frameshift mutations in coding mononucleotide tracts were detected in BAX (6 of 7), IGFIIR (1 of 7), and MSH3 (2 of 7). MLH‐1 promoter hypermethylation was identified in three of six MI positive tumors. CONCLUSIONS Microsatellite instability was infrequent in this series of ovarian tumors, and it was limited to endometrioid and clear cell carcinomas. Like EC, many ovarian carcinomas with MI follow the same process of MLH‐1 promoter methylation and accumulation of mutations in coding mononucleotide tracts. Cancer 2001;92:2829–36. © 2001 American Cancer Society.

BACKGROUND BRCA‐1 and BRCA‐2 are tumor suppressor genes in familial breast‐ovarian carcinoma syndrome. BRCA‐1 is also a tumor suppressor gene in sporadic ovarian carcinomas. However, the role of BRCA‐2 in sporadic ovarian tumors remains unclear. METHODS DNA from 52 patients with clinically apparent sporadic ovarian tumors was extracted from blood and from fresh‐frozen tumor tissue and normal tissue (10 benign, 7 borderline, and 35 malignant). Loss of heterozygosity (LOH) was analyzed in six microsatellite loci on chromosome 13q. BRCA‐2 mutations were detected by single‐strand conformation polymorphism analysis and the protein truncation test. BRCA‐2 promoter methylation was evaluated by methylation specific polymerase chain reaction analysis. RESULTS LOH on chromosome 13q12–q14 was identified in 16 tumors (30.8%): Fifteen of these tumors were carcinomas (15 of 35 tumors; 42.8%) and one was a borderline tumor. LOH was frequent in carcinomas with serous differentiation (12 of 16 tumors; 75%). LOH on chromosome 13q12–q14 coexisted with LOH on chromosome 17q in 10 carcinomas. BRCA‐2 methylation was not detected in any tumor. BRCA‐2 mutations were found in three tumors (one somatic nonsense and two germline frameshift). BRCA‐2 fulfilled the two hits for a tumor suppressor gene in these three tumors; in one of them, a BRCA‐1 tumor suppressor role had been demonstrated previously. CONCLUSIONS The results suggest that BRCA‐1 and BRCA‐2 may act synergically in sporadic ovarian carcinomas with serous differentiation. The demonstration of BRCA‐2 germline mutations in patients with ovarian carcinoma with LOH on chromosome 13q12–q14 and lack of a remarkable family history of cancer suggest that the proportion of ovarian carcinomas that result from hereditary predisposition may be higher than previously estimated. Cancer 2001;92:787–95. © 2001 American Cancer Society.

The paucicellular variant of anaplastic carcinoma is an infrequent type of thyroid tumor. It was described as a tumor characterized by very low cellularity and prominent fibrosis, probably secondary...

K‐ras mutations are known to occur in hyperplasias and carcinomas of the endometrium. No clear correlation has been found yet between K‐ras mutations and microsatellite instability (MI) in these lesions. Fifty‐eight endometrial carcinomas (ECs) and 22 endometrial hyperplasias (EHs) were analysed for K‐ras mutation by single‐strand conformational polymorphism analysis (SSCP), restriction analysis, and DNA sequencing. MI status had been established previously at five dinucleotide loci and was reconfirmed with markers BAT‐25 and BAT‐26 by SSCP. K‐ras mutations were detected in 11 ECs (18.9%). All 11 tumours were endometrioid carcinomas. K‐ras mutations were more frequent in MI‐positive (6/14, 42.8%) than in MI‐negative tumours (5/44, 11.3%) (p=0.017). Methylation‐related transitions were detected in five of the six MI‐positive tumours but in only one of the five MI‐negative carcinomas. K‐ras mutation was identified in only one atypical EH (1/22, 4.5%); in this case, the EH co‐existed with EC and both lesions exhibited MI. The results support a close relationship between K‐ras mutations and the phenomenon of MI in endometrial carcinomas. The frequent occurrence of methylation‐related transitions in these tumours may indicate a cause–effect relationship with the altered methylation status which has been described in association with MI. Copyright © 2000 John Wiley & Sons, Ltd.