RESUMEN
OBJECTIVE: Ovarian cancer is known for its poor prognosis, which is mainly due to the lack of early symptoms and adequate screening options. In this study we evaluated whether mutational analysis in cervicovaginal and endometrial samples could assist in the detection of ovarian cancer. METHODS: In this prospective multicenter study, we included patients surgically treated for either (suspicion of) ovarian cancer or for a benign gynecological condition (control group). A cervicovaginal self-sample, a Papanicolaou (Pap) smear, a pipelle endometrial biopsy, and the surgical specimen were analyzed for (potentially) pathogenic variants in eight genes (ARID1A, CTNNB1, KRAS, MTOR, PIK3CA, POLE, PTEN, and TP53) using single-molecule molecular inversion probes. Sensitivity and specificity were calculated to assess diagnostic accuracy. RESULTS: Based on surgical histology, our dataset comprised 29 patients with ovarian cancer and 32 controls. In 83% of the patients with ovarian cancer, somatic (potentially) pathogenic variants could be detected in the final surgical specimen, of which 71% included at least a TP53 variant. In 52% of the ovarian cancer patients, such variants could be detected in either the self-sample, Pap smear, or pipelle. The Pap smear yielded the highest diagnostic accuracy with 26% sensitivity (95% CI 10% to 48%). Overall diagnostic accuracy was low and was not improved when including TP53 variants only. CONCLUSIONS: Mutational analysis in cervicovaginal and endometrial samples has limited accuracy in the detection of ovarian cancer. Future research with cytologic samples analyzed on methylation status or the vaginal microbiome may be relevant.
Asunto(s)
Neoplasias Endometriales , Neoplasias Ováricas , Humanos , Femenino , Estudios Prospectivos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Prueba de Papanicolaou , Endometrio/patología , Vagina/patología , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patologíaRESUMEN
Patients synchronously or metachronously presenting with ovarian and colon cancer can pose diagnostic challenges. A primary colon carcinoma can metastasize to one or both ovaries, two independent primary tumors can arise or an ovarian carcinoma can metastasize to the colon. Clinical and immunohistochemical characterization can aid the diagnosis. Recently, we reported that in difficult cases finding pathogenic APC variants supports a colonic origin.In this case report we describe the clinical history of a female patient suspected for Lynch syndrome. She was diagnosed with a bilateral ovarian cancer at age 44, followed by the detection of a colon carcinoma 12.5 months later. Lesions of both sites showed a DNA mismatch repair deficiency with immunohistochemical loss of MLH1 and PMS2 expression without MLH1 promoter hypermethylation. In absence of germline MMR gene variants identical somatic MLH1 and CTNNB1 gene variants were found, indicating a clonal relation. MMR germline mosaicism was made unlikely by ultra deep sequencing of the MLH1 variant in DNA isolated from normal mucosa, blood, urine and saliva. Although initially being suspect for Lynch syndrome it was eventually concluded that a metachronously diagnosed colon carcinoma that metastasized to both ovaries was most likely.
Asunto(s)
Neoplasias del Colon/genética , Reparación de la Incompatibilidad de ADN/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias Primarias Múltiples/genética , Neoplasias Ováricas/genética , Adulto , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Femenino , Humanos , Persona de Mediana EdadRESUMEN
AIMS: Lynch syndrome-associated tumours are characterized by the presence of an increased number of tumour-infiltrating lymphocytes. This enhanced lymphocytic response may be elicited by genetically altered proteins that may arise as a result of a defective DNA mismatch repair system. The aim was to investigate this hypothesis by correlating loss of mismatch repair proteins and infiltration of lymphocytes in Lynch syndrome-associated adenomas and hyperplastic polyps. METHODS AND RESULTS: Mismatch repair protein expression and the number of tumour-infiltrating lymphocytes were assessed in Lynch syndrome (41 adenomas and nine hyperplastic polyps) and in familial colorectal cancer (nine adenomas and one hyperplastic polyp). Nineteen sporadic adenomas were included as a control group. Twenty of 32 (63%) adenomas with loss of mismatch repair protein expression showed an increase in tumour-infiltrating lymphocytes. Eight adenomas (8/32; 25%) displayed many tumour-infiltrating lymphocytes, whereas most adenomas (12/32; 38%) showed a minor increase. In adenomas with mismatch repair protein expression, both sporadic and Lynch syndrome associated, not one showed an increased number of tumour-infiltrating lymphocytes. Hyperplastic polyps in Lynch syndrome patients showed neither loss of mismatch repair expression nor an increase in tumour-infiltrating lymphocytes. CONCLUSIONS: There is a correlation between the loss of mismatch repair proteins and the infiltration of lymphocytes in Lynch syndrome-associated adenomas.
Asunto(s)
Adenoma/metabolismo , Adenoma/patología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/metabolismo , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Enzimas Reparadoras del ADN/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenoma/genética , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Estudios de Casos y Controles , Neoplasias del Colon/genética , Pólipos del Colon/genética , Pólipos del Colon/metabolismo , Pólipos del Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Enzimas Reparadoras del ADN/genética , ADN de Neoplasias/genética , ADN de Neoplasias/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Mutación de Línea Germinal/genética , Humanos , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMEN
The frame-shifting mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be associated with familial breast cancer in families in which mutations in BRCA1 and BRCA2 were excluded. To investigate the role of this variant as a candidate breast cancer susceptibility allele, we determined its prevalence in 237 breast cancer patients and 331 healthy relatives derived from 71 non-BRCA1/BRCA2 multiple-case early onset breast cancer families. Twenty-seven patients (11.4%) were carrying the CHEK2*1100delC variant. At least one carrier was found in 15 of the 71 families (21.1%). There was no evidence of cosegregation between the variant and breast cancer, but carrier patients developed breast cancer earlier than did noncarriers. We studied CHEK2 protein expression in 111, and loss of heterozygosity at CHEK2 in 88 breast tumors from these patients. Twelve of 15 tumors from carriers showed absent protein expression as opposed to 3 of 76 tumors from noncarriers (P < 0.001). CHEK2 loss of heterozygosity was associated with absence of protein expression but not with 1100delC carrier status. Thus, selecting for breast cancer cases with a strong familial background not accounted for by BRCA1 or BRCA2 strongly enriches for carriers of CHEK2*1100delC. Our results support a model in which CHEK2*1100delC interacts with an as yet unknown gene (or genes) to increase breast cancer risk.