RESUMO
Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA/genética , Neoplasias Colorretais/genética , Síndromes Neoplásicas Hereditárias/genética , Proteína 1 Homóloga a MutL/genética , Metilação de DNA/genética , Instabilidade de MicrossatélitesRESUMO
Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n=137; 80xCRCs, 33xECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.
RESUMO
BACKGROUND: Muir-Torre syndrome is defined by the development of sebaceous skin lesions in individuals who carry a germline mismatch repair (MMR) gene mutation. Loss of expression of MMR proteins is frequently observed in sebaceous skin lesions, but MMR-deficiency alone is not diagnostic for carrying a germline MMR gene mutation. METHODS: Whole exome sequencing was performed on three MMR-deficient sebaceous lesions from individuals with MSH2 gene mutations (Lynch syndrome) and three MMR-proficient sebaceous lesions from individuals without Lynch syndrome with the aim of characterizing the tumor mutational signatures, somatic mutation burden, and microsatellite instability status. Thirty predefined somatic mutational signatures were calculated for each lesion. RESULTS: Signature 1 was ubiquitous across the six lesions tested. Signatures 6 and 15, associated with defective DNA MMR, were significantly more prevalent in the MMR-deficient lesions from the MSH2 carriers compared with the MMR-proficient non-Lynch sebaceous lesions (mean ± SD=41.0 ± 8.2% vs. 2.3 ± 4.0%, p = 0.0018). Tumor mutation burden was, on average, significantly higher in the MMR-deficient lesions compared with the MMR-proficient lesions (23.3 ± 11.4 vs. 1.8 ± 0.8 mutations/Mb, p = 0.03). All four sebaceous lesions observed in sun exposed areas of the body demonstrated signature 7 related to ultraviolet light exposure. CONCLUSION: Tumor mutational signatures 6 and 15 and somatic mutation burden were effective in differentiating Lynch-related from non-Lynch sebaceous lesions.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Síndrome de Muir-Torre/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Biomarcadores Tumorais , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/metabolismo , Mutação , Proteínas Nucleares/genética , Transcriptoma/genética , Sequenciamento do Exoma/métodosAssuntos
Carcinoma de Células Escamosas/patologia , Doenças Negligenciadas/complicações , Metástase Neoplásica/patologia , Neoplasias Cutâneas/patologia , Parede Torácica/patologia , Doença de Bowen/patologia , Evolução Fatal , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/secundário , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Parede Torácica/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Different reports from Middle East countries demonstrated Kaposi's sarcoma (KS) in transplant population. This vascular malignancy occurs mostly among immunocompromised individuals. Human herpesvirus 8 (HHV-8) appears to be the causative factor for the development of this neoplasm. Transplant programs are concerned about the frequencies of HHV-8 infection either in general population or transplant patients. METHODS: The current study was conducted in two phases. Firstly, we detected antibodies against HHV-8 in 790 otherwise healthy blood donors. Secondly, a total of 125 kidney allograft recipients evaluated as being seropositive for HHV-8. We utilized enzyme immunoassay (EIA) for serologic studies. RESULTS: Among blood donors, the male to female ratio was 1.05 (405 vs. 385 ) while the mean age was 38.9 ± 11.7 years. The serostatus of none of these blood donors were positive for HHV-8. Among kidney recipients, the male to female ratio was 1.9 (82 vs. 43). The mean age was 39.01 ± 14.77 years. Two (1.6%) patients were seropositive for HHV-8. CONCLUSION: The prevalence of HHV-8 infection among Iranians is likely to be low. Yet, owing to the evidence of this infection among kidney allograft recipients and its probable role in developing post- transplantation KS (PT-KS), further studies appear to be required to keep the various aspects of this infection under close surveillance.