Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers - PubMed (original) (raw)

Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers

Paul J Goodfellow et al. Proc Natl Acad Sci U S A. 2003.

Abstract

Endometrial cancer is the most common gynecologic malignancy in the United States and the most frequent extracolonic tumor in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC patients have inherited defects in DNA mismatch repair and the microsatellite instability (MSI) tumor phenotype. Sporadic endometrial cancers also exhibit MSI, usually associated with methylation of the MLH1 promoter. Germ-line MSH6 mutations, which are rare in HNPCC, have been reported in several families with multiple members affected with endometrial carcinoma. We reasoned that MSH6 mutation might account for loss of mismatch repair in MSI-positive endometrial cancers in which the cause of MSI is unknown. We therefore investigated MSI and MLH1 promoter methylation in 441 endometrial cancer patients unselected for age or personal and family history of cancers. MSI and MLH1 promoter methylation status were associated with age of onset and tumor histology. One hundred cases (23% of the entire series) were evaluated for MSH6 defects. Inactivating germ-line MSH6 mutations were identified in seven women with MSI-positive, MLH1 promoter unmethylated cancers. Most of the MSI in these cases was seen with mononucleotide repeat markers. The MSH6 mutation carriers were significantly younger than the rest of the population (mean age 54.8 versus 64.6, P = 0.04). Somatic mutations were seen in 17 tumors, all of which had MSI. Our data suggest that inherited defects in MSH6 in women with endometrial cancer are relatively common. The minimum estimate of the prevalence of inherited MSH6 mutation in endometrial cancer is 1.6% (7 of 441), comparable with the predicted prevalence for patients with colorectal cancer.

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Figures

Figure 1

Figure 1

Flow diagram for results of testing for defects in DNA mismatch repair in 441 unselected patients with endometrial cancer. All tumors were assessed for MSI, and those with MSI were evaluated for MLH1 promoter methylation. Among the 35 cases lacking MLH1 methylation, five were previously shown to have germ-line MSH2 mutations (ref. and our unpublished data). The remaining 30 cases, classified as MSI-H unmethylated, were assessed for MSH6 mutations along with 10 MSI-L, 30 MSI-H methylated, and 30 MSS cases.

Figure 2

Figure 2

Association between MSI status and MLH1 promoter methylation and age at diagnosis and tumor type. (A) Box plot showing the distribution of ages among women with MSI-H unmethylated, MSI-H methylated, MSI-L, and MSS tumors. Boxes include the 25th through 75th centile for each group, and the median for each is shown with a horizontal bar. (B) Proportions of each group with onset of endometrial cancer before age 50. (C) Proportion of each group with nonendometrioid tumors (papillary serous, clear cell, or mixed histologies). MSI-H U, MSI-H MLH1 promoter unmethylated; MSI-H M, MSI-H MLH1 promoter methylated.

Figure 3

Figure 3

Germ-line mutations in endometrial cancer patients. (A) Representative DNA sequence analyses reveal mutations in exon 9. The overlapping sequences reflect a deletion in patient 1319 and an insertion in patient 1524. (B) Single base C → T substitution at codon 911 in patient 1497. Reverse sequence is shown (G → A). (C) Alignment of MSH6 peptide sequence with the Ala insertion in case 1064 within the ATPase domain of DNA mismatch repair MUTS family. Conserved amino acids are shown in red. The Ala insertion (A), marked with an asterisk, disrupts at the conserved VPAE sequence.

Figure 4

Figure 4

Reduced numbers of MSI events involving dinucleotide repeats in tumors from women with inherited MSH6 mutations. The rates of MSI at each of the five markers tested are compared for MSH6 mutation carriers (n = 7) and the 53 other cases classified as MSI-H. The combined number of MSI events seen with dinucleotide repeat markers (D2S123, D5S346, and D17S250) is significantly less in MSH6 mutation carriers than in the other MSI-H cases (P < 0.001, Fisher's exact test). NS, not significant.

Figure 5

Figure 5

Somatic MSH6 deletion in tumor 1335. (A) Germ-line C → T mutation at codon 911 (Arg911Stop) is heterozygous in the normal cellular DNA. (B) Allelic deletion in tumor 1335. Patient 1335 is heterozygous for the intron 5 variant detected by SSCV. Arrowheads indicate bands that reveal loss of heterozygosity.

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