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HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression.

Dierssen JW, de Miranda NF, Ferrone S, van Puijenbroek M, Cornelisse CJ, Fleuren GJ, van Wezel T, Morreau H - BMC Cancer (2007)

Bottom Line: In about half of the cases, loss of expression of HLA class I was concordant with the detection of one or more mutations in the beta2m and APM components genes.HLA class I aberrations are found at varying frequencies in different colorectal tumor types and are caused by distinct genetic mechanisms.The resulting variation in immune escape mechanisms may have repercussions in tumor progression and behavior.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. JWFDierssen@gmail.com <JWFDierssen@gmail.com>

ABSTRACT

Background: Abnormalities in Human Leukocyte Antigen (HLA) class I expression are common in colorectal cancer. Since HLA expression is required to activate tumor antigen-specific cytotoxic T-lymphocytes (CTL), HLA class I abnormalities represent a mechanism by which tumors circumvent immune surveillance. Tumors with high microsatellite instability (MSI-H) are believed to face strong selective pressure to evade CTL activity since they produce large amounts of immunogenic peptides. Previous studies identified the prevalence of HLA class I alterations in MSI-H tumors. However, those reports did not compare the frequency of alterations between hereditary and sporadic MSI-H tumors neither the mechanisms that led to HLA class I alterations in each subgroup.

Methods: To characterize the HLA class I expression among sporadic MSI-H and microsatellite-stable (MSS) tumors, and HNPCC tumors we compared immunohistochemically the expression of HLA class I, beta2-microglobulin (beta2m), and Antigen Processing Machinery (APM) components in 81 right-sided sporadic and 75 HNPCC tumors. Moreover, we investigated the genetic basis for these changes.

Results: HLA class I loss was seen more frequently in MSI-H tumors than in MSS tumors (p < 0.0001). Distinct mechanisms were responsible for HLA class I loss in HNPCC and sporadic MSI-H tumors. Loss of HLA class I expression was associated with beta2m loss in HNPCC tumors, but was correlated with APM component defects in sporadic MSI-H tumors (p < 0.0001). In about half of the cases, loss of expression of HLA class I was concordant with the detection of one or more mutations in the beta2m and APM components genes.

Conclusion: HLA class I aberrations are found at varying frequencies in different colorectal tumor types and are caused by distinct genetic mechanisms. Chiefly, sporadic and hereditary MSI-H tumors follow different routes toward HLA class I loss of expression supporting the idea that these tumors follow different evolutionary pathways in tumorigenesis. The resulting variation in immune escape mechanisms may have repercussions in tumor progression and behavior.

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LOH and frameshift analysis was performed on sporadic RST that lost HLA class I expression. Only the tumors that presented with loss of one of the APM molecules or β2m were subjected to fragment analysis in their respective genes. The following repeats were analyzed for frameshift mutations: HLA A: 1 – 4th exon 7(C), 2 – 5th exon 3 (GGA); HLA – B: 3(GA) & 3(CA);β2m: 1 – 1st exon 4(CT), 2 – 2nd exon 4(GA) & 5(A), 3 – 2nd exon 5(A); TAP1: 1 – 1st exon 5(C), 2 – 3rd exon 5(T), 3 – 8th exon 5(G), 4 – 10th exon 5(G), 5 – 11th exon 6(G) & 5(A); TAP2: 1 – 2nd exon 6(C), 2 – 9th exon 5(G); Tapasin: 1 – 2nd exon 5(G), 2 – 3rd exon 5(C), 3 – 4th exon 6(C), 4 – 5th exon 5(G); Calnexin: 1 – 7th exon 5(A), 2 – 8th exon 5(A), 3 – 11th exon 8(T); Calreticulin: 1 – 3rd exon 5(G), 6th exon 5(C); ERp57: 1 – 5th exon 6(T), 2 – 6th exon 6(A), 3 – 13th exon 6(C); LMP2: 1 – 2nd exon 5(G), 2 – 6th exon 5(G); LMP7: 1st exon 6(C) (key: ins – insertion; del – deletion; 0 – no mutation). LOH analysis of the 6p chromosome was also performed with the following markers: 1 – MOGc, 2 – D6S510, 3 – C125, 4 – C141, 5 – D6S2444, 6 – TAP1, 7 – M2426 (Key: Black – Loss of heterozygosity; Striped – non informative marker; White – Retention of heterozygosity).
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Figure 3: LOH and frameshift analysis was performed on sporadic RST that lost HLA class I expression. Only the tumors that presented with loss of one of the APM molecules or β2m were subjected to fragment analysis in their respective genes. The following repeats were analyzed for frameshift mutations: HLA A: 1 – 4th exon 7(C), 2 – 5th exon 3 (GGA); HLA – B: 3(GA) & 3(CA);β2m: 1 – 1st exon 4(CT), 2 – 2nd exon 4(GA) & 5(A), 3 – 2nd exon 5(A); TAP1: 1 – 1st exon 5(C), 2 – 3rd exon 5(T), 3 – 8th exon 5(G), 4 – 10th exon 5(G), 5 – 11th exon 6(G) & 5(A); TAP2: 1 – 2nd exon 6(C), 2 – 9th exon 5(G); Tapasin: 1 – 2nd exon 5(G), 2 – 3rd exon 5(C), 3 – 4th exon 6(C), 4 – 5th exon 5(G); Calnexin: 1 – 7th exon 5(A), 2 – 8th exon 5(A), 3 – 11th exon 8(T); Calreticulin: 1 – 3rd exon 5(G), 6th exon 5(C); ERp57: 1 – 5th exon 6(T), 2 – 6th exon 6(A), 3 – 13th exon 6(C); LMP2: 1 – 2nd exon 5(G), 2 – 6th exon 5(G); LMP7: 1st exon 6(C) (key: ins – insertion; del – deletion; 0 – no mutation). LOH analysis of the 6p chromosome was also performed with the following markers: 1 – MOGc, 2 – D6S510, 3 – C125, 4 – C141, 5 – D6S2444, 6 – TAP1, 7 – M2426 (Key: Black – Loss of heterozygosity; Striped – non informative marker; White – Retention of heterozygosity).

Mentions: Polymorphic markers around the classical HLA genes (A, B and C), TAP 1 and TAP2 genes were used to study LOH and reveal possible chromosomal aberrations that could relate to loss of HLA class I expression (Figure 5A). In HNPCC cases, LOH analysis was only performed around the HLA genes since loss of the TAP1 and TAP2 proteins was rarely associated with HLA class I loss. LOH was more frequent in the MSS tumors (50%) than in the MSI-H sporadic (20%) and HNPCC (6%) tumors with loss of HLA class I expression (P < 0.05) (Figure 3, 4). Furthermore, the patterns of LOH in the MSS cases might indicate loss of the entire 6p21.3 region, in contrast to the MSI-H cases (hereditary and sporadic forms) where LOH seems to be limited.


HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression.

Dierssen JW, de Miranda NF, Ferrone S, van Puijenbroek M, Cornelisse CJ, Fleuren GJ, van Wezel T, Morreau H - BMC Cancer (2007)

LOH and frameshift analysis was performed on sporadic RST that lost HLA class I expression. Only the tumors that presented with loss of one of the APM molecules or β2m were subjected to fragment analysis in their respective genes. The following repeats were analyzed for frameshift mutations: HLA A: 1 – 4th exon 7(C), 2 – 5th exon 3 (GGA); HLA – B: 3(GA) & 3(CA);β2m: 1 – 1st exon 4(CT), 2 – 2nd exon 4(GA) & 5(A), 3 – 2nd exon 5(A); TAP1: 1 – 1st exon 5(C), 2 – 3rd exon 5(T), 3 – 8th exon 5(G), 4 – 10th exon 5(G), 5 – 11th exon 6(G) & 5(A); TAP2: 1 – 2nd exon 6(C), 2 – 9th exon 5(G); Tapasin: 1 – 2nd exon 5(G), 2 – 3rd exon 5(C), 3 – 4th exon 6(C), 4 – 5th exon 5(G); Calnexin: 1 – 7th exon 5(A), 2 – 8th exon 5(A), 3 – 11th exon 8(T); Calreticulin: 1 – 3rd exon 5(G), 6th exon 5(C); ERp57: 1 – 5th exon 6(T), 2 – 6th exon 6(A), 3 – 13th exon 6(C); LMP2: 1 – 2nd exon 5(G), 2 – 6th exon 5(G); LMP7: 1st exon 6(C) (key: ins – insertion; del – deletion; 0 – no mutation). LOH analysis of the 6p chromosome was also performed with the following markers: 1 – MOGc, 2 – D6S510, 3 – C125, 4 – C141, 5 – D6S2444, 6 – TAP1, 7 – M2426 (Key: Black – Loss of heterozygosity; Striped – non informative marker; White – Retention of heterozygosity).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808468&req=5

Figure 3: LOH and frameshift analysis was performed on sporadic RST that lost HLA class I expression. Only the tumors that presented with loss of one of the APM molecules or β2m were subjected to fragment analysis in their respective genes. The following repeats were analyzed for frameshift mutations: HLA A: 1 – 4th exon 7(C), 2 – 5th exon 3 (GGA); HLA – B: 3(GA) & 3(CA);β2m: 1 – 1st exon 4(CT), 2 – 2nd exon 4(GA) & 5(A), 3 – 2nd exon 5(A); TAP1: 1 – 1st exon 5(C), 2 – 3rd exon 5(T), 3 – 8th exon 5(G), 4 – 10th exon 5(G), 5 – 11th exon 6(G) & 5(A); TAP2: 1 – 2nd exon 6(C), 2 – 9th exon 5(G); Tapasin: 1 – 2nd exon 5(G), 2 – 3rd exon 5(C), 3 – 4th exon 6(C), 4 – 5th exon 5(G); Calnexin: 1 – 7th exon 5(A), 2 – 8th exon 5(A), 3 – 11th exon 8(T); Calreticulin: 1 – 3rd exon 5(G), 6th exon 5(C); ERp57: 1 – 5th exon 6(T), 2 – 6th exon 6(A), 3 – 13th exon 6(C); LMP2: 1 – 2nd exon 5(G), 2 – 6th exon 5(G); LMP7: 1st exon 6(C) (key: ins – insertion; del – deletion; 0 – no mutation). LOH analysis of the 6p chromosome was also performed with the following markers: 1 – MOGc, 2 – D6S510, 3 – C125, 4 – C141, 5 – D6S2444, 6 – TAP1, 7 – M2426 (Key: Black – Loss of heterozygosity; Striped – non informative marker; White – Retention of heterozygosity).
Mentions: Polymorphic markers around the classical HLA genes (A, B and C), TAP 1 and TAP2 genes were used to study LOH and reveal possible chromosomal aberrations that could relate to loss of HLA class I expression (Figure 5A). In HNPCC cases, LOH analysis was only performed around the HLA genes since loss of the TAP1 and TAP2 proteins was rarely associated with HLA class I loss. LOH was more frequent in the MSS tumors (50%) than in the MSI-H sporadic (20%) and HNPCC (6%) tumors with loss of HLA class I expression (P < 0.05) (Figure 3, 4). Furthermore, the patterns of LOH in the MSS cases might indicate loss of the entire 6p21.3 region, in contrast to the MSI-H cases (hereditary and sporadic forms) where LOH seems to be limited.

Bottom Line: In about half of the cases, loss of expression of HLA class I was concordant with the detection of one or more mutations in the beta2m and APM components genes.HLA class I aberrations are found at varying frequencies in different colorectal tumor types and are caused by distinct genetic mechanisms.The resulting variation in immune escape mechanisms may have repercussions in tumor progression and behavior.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. JWFDierssen@gmail.com <JWFDierssen@gmail.com>

ABSTRACT

Background: Abnormalities in Human Leukocyte Antigen (HLA) class I expression are common in colorectal cancer. Since HLA expression is required to activate tumor antigen-specific cytotoxic T-lymphocytes (CTL), HLA class I abnormalities represent a mechanism by which tumors circumvent immune surveillance. Tumors with high microsatellite instability (MSI-H) are believed to face strong selective pressure to evade CTL activity since they produce large amounts of immunogenic peptides. Previous studies identified the prevalence of HLA class I alterations in MSI-H tumors. However, those reports did not compare the frequency of alterations between hereditary and sporadic MSI-H tumors neither the mechanisms that led to HLA class I alterations in each subgroup.

Methods: To characterize the HLA class I expression among sporadic MSI-H and microsatellite-stable (MSS) tumors, and HNPCC tumors we compared immunohistochemically the expression of HLA class I, beta2-microglobulin (beta2m), and Antigen Processing Machinery (APM) components in 81 right-sided sporadic and 75 HNPCC tumors. Moreover, we investigated the genetic basis for these changes.

Results: HLA class I loss was seen more frequently in MSI-H tumors than in MSS tumors (p < 0.0001). Distinct mechanisms were responsible for HLA class I loss in HNPCC and sporadic MSI-H tumors. Loss of HLA class I expression was associated with beta2m loss in HNPCC tumors, but was correlated with APM component defects in sporadic MSI-H tumors (p < 0.0001). In about half of the cases, loss of expression of HLA class I was concordant with the detection of one or more mutations in the beta2m and APM components genes.

Conclusion: HLA class I aberrations are found at varying frequencies in different colorectal tumor types and are caused by distinct genetic mechanisms. Chiefly, sporadic and hereditary MSI-H tumors follow different routes toward HLA class I loss of expression supporting the idea that these tumors follow different evolutionary pathways in tumorigenesis. The resulting variation in immune escape mechanisms may have repercussions in tumor progression and behavior.

Show MeSH
Related in: MedlinePlus