Current Oncology, Vol. 30, Pages 75-84: Solid Organ Transplantation Is Associated with an Increased Rate of Mismatch Repair Deficiency and PIK3CA Mutations in Colorectal Cancer

Figure 1. There is an increased proportion of mismatch repair deficient tumors and right-sided in the post-transplant population. We hypothesized that given the proposed role of the immune system in reducing relapse risk in mismatch repair deficient tumors many of these immunogenic tumors may be cleared before becoming clinically apparent. We suspected, therefore, that an increased proportion of tumors that developed in post-transplant patients would be mismatch repair deficient (MMRd). To test this, we identified 17 post-transplant CRC patients that with tumor mismatch repair testing. Of these, 7 (41%) were MMRd which is higher than the general population. Right-sided tumors also show higher degrees of tumor infiltrating lymphocytes suggesting that they may be better recognized by the immune system. We noted that our post-transplant population had a higher rate of right-sided tumors (20/29 or 69%) than the general population.

Figure 1. There is an increased proportion of mismatch repair deficient tumors and right-sided in the post-transplant population. We hypothesized that given the proposed role of the immune system in reducing relapse risk in mismatch repair deficient tumors many of these immunogenic tumors may be cleared before becoming clinically apparent. We suspected, therefore, that an increased proportion of tumors that developed in post-transplant patients would be mismatch repair deficient (MMRd). To test this, we identified 17 post-transplant CRC patients that with tumor mismatch repair testing. Of these, 7 (41%) were MMRd which is higher than the general population. Right-sided tumors also show higher degrees of tumor infiltrating lymphocytes suggesting that they may be better recognized by the immune system. We noted that our post-transplant population had a higher rate of right-sided tumors (20/29 or 69%) than the general population.

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Figure 2. Comparing the absolute lymphocyte count between mismatch proficient and deficient colorectal cancer in transplant population. A total of 15 patients within our cohort had absolute lymphocyte counts (ALC) carried out at the time of their diagnosis along with mismatch repair status determination and tumor mutation burden. Of these, 8 patients were mismatch repair proficient (pMMR) and the other 7 patients were mismatch repair deficient (MMRd). The pMMR tumors had a higher ALC (median: 1.20, mean: 1.55) then the MMRd tumors (median: 0.48, mean: 0.57) which was statistically significant (student’s t-test: p-value = 0.009).

Figure 2. Comparing the absolute lymphocyte count between mismatch proficient and deficient colorectal cancer in transplant population. A total of 15 patients within our cohort had absolute lymphocyte counts (ALC) carried out at the time of their diagnosis along with mismatch repair status determination and tumor mutation burden. Of these, 8 patients were mismatch repair proficient (pMMR) and the other 7 patients were mismatch repair deficient (MMRd). The pMMR tumors had a higher ALC (median: 1.20, mean: 1.55) then the MMRd tumors (median: 0.48, mean: 0.57) which was statistically significant (student’s t-test: p-value = 0.009).

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Figure 3. The distribution of PI3 Kinase-mTOR Mutations in Post-transplant and General Populations diagnosed with Colorectal Cancer (CRC). We identified 14 patients in our post-transplant population who had molecular profiling. Of them, 6 (44%; 95% CI, 18–71%) had PIK3CA which is significantly increased by Fisher’s exact test (p = 0.042) compared to a 24% prevalence in a general CRC population.

Figure 3. The distribution of PI3 Kinase-mTOR Mutations in Post-transplant and General Populations diagnosed with Colorectal Cancer (CRC). We identified 14 patients in our post-transplant population who had molecular profiling. Of them, 6 (44%; 95% CI, 18–71%) had PIK3CA which is significantly increased by Fisher’s exact test (p = 0.042) compared to a 24% prevalence in a general CRC population.

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Table 1. The demographics of Post-Transplant Patients that Developed Colorectal Cancer.

Table 1. The demographics of Post-Transplant Patients that Developed Colorectal Cancer.

All Patients (n = 29)Kidney (n = 18)Liver (n = 8)KLT (n = 3)Age in years (range) 60 (31–82)51 (31–77)62.5 (54–73)73 (66–82)Sex (%)Male16 (55)10 (56)4 (50)2 (67) Female13 (45)8 (44)4 (50)1 (33)Time from transplant to CRC diagnosis in years 9 (2–35)11 (3–35)3.5 (2–13)6 (2–12)TMB median (range) 21.98 (3.52–53.7)14.07 (3.52–31.7)45.8 (37.8–53.7)37Mismatch Repair Status (%)MMRd7 (41)3 (27)2 (50)2 (100) pMMR10 (59)8 (63)2 (50)0ALC at CRC dx (K/μL) median/range 1.1 (0.25–2.99)1.2 (0.48–2.99)0.84 (0.25–2.1)0.86 (0.83–1.43)PIK3CA status (%)Mutant6 (43)3 (38)2 (50)1 (50) Wild type8 (57)5 (62)2 (50)1 (50)KRAS status (%)Mutant3 (21)2 (25)01 (50) Wild type11 (79)6 (75)2 (100)1 (50)BRAF status (%)Mutant4 (31)1 (14)2 (50)1 (50) Wild type9 (69)6 (86)2 (50)1 (50)APC status (%)Mutant5 (42)4 (57)01 (100) Wild type7 (58)3 (43)4 (100)0TP53 status (%)Mutant5 (42)3 (43)2 (50)0 Wild type7 (58)4 (57)2 (50)1 (100)Immunosuppression at the time of CRC diagnosis (%)none2 (7)2 (11)00CNI6 (21)1 (6)5 (62)0CNI + MMF1 (3)01 (12)0CNI + Pred7 (24)6 (33)01 (33)CNI + MMF + Pred9 (30)7 (39)02 (67)CNI + Pred + 6-MP1 (3)01 (12)0mTORi + MMF1 (3)01 (12)0mTORi + Pred1 (3)1 (6)00AZA + Pred1 (3)1 (6)00Cause of Liver Transplant (%)HCV3 (27)N/A2 (25)1 (33)ETOH3 (27)N/A2 (25)1 (33)NASH3 (27)N/A2 (25)1 (33)Primary Sclerosing Cholangitis1 (9)N/A1 (12)0Alpha-1-Antitrypsin1 (9)N/A1 (12)0Cause of Renal Transplant (%)atypical HUS1 (5)1 (6)N/A0CNI toxicity1 (5)0N/A1(33)diarrhea 2/2 short gut1 (5)0N/A1 (33)DM4 (19)4 (22)N/A0DM/HTN1 (5)1 (6)N/A0DM/FSGS1 (5)1 (6)N/A0FSGS2 (10)2 (11)N/A0GPA1 (5)1 (6)N/A0HTN4 (19)3 (17)N/A1 (33)IgA nephropathy1 (5)1 (6)N/A0oligomeganephronia1 (5)1 (6)N/A0PKD1 (5)1 (6)N/A0SLE2 (10)2 (11)N/A0Stage at diagnosis (%)Stage 0/17 (24)5 (28)2 (25)0 Stage 29 (31)6 (33)1 (12)2 (67) Stage 310 (34)5 (28)4 (50)1 (33) Stage 43 (10)2 (11)1 (12)0Recurrence (%)Yes7 (24)6 (33)01 (33) No22 (76)12 (67)8 (100)2 (67)Tumor location Right20 (69)12 (67)5 (62)3 (100) Left5 (17)3 (17)2 (25)0 Rectal4 (14)3 (17)1 (12)0

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