| 1. |
- Koul, Anjila, et al.
(författare)
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Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis
- 2002
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Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 94:9, s. 2369-2379
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Endometrial carcinomas seem to carry a different prognosis depending on the presence or absence of concomitant complex atypical hyperplasia (hyperplasia). The molecular genetic profile of these two pathogenetic types, based on the genes reportedly mutated in these cancers, remains to be defined. Although microsatellite inability is reported in approximately 25% of endometrial carcinomas, its relation with the 2 pathogenetic types is not investigated. METHODS. To elucidate their underlying genetic changes, we analyzed 53 sporadic endometrial tumors, including 19 with and 34 without hyperplasia, for microsatellite instability (MSI), DNA ploidy (by flow cytometry), and for mutations in different genes. RESULTS. Microsatellite instability was present in 21%, DNA nondiploidy in 15%, and mutations in the PTEN, KRAS, CTNNB1/beta-catenin, TP53, and CDKN2A genes were detected in 32, 11, 13, 17, and 0% of the tumors, respectively. Microsatellite instability and mutations in these genes were present in tumors both with and without complex atypical hyperplasia. All cases with complex atypical hyperplasia were early stage (I-II) endometrioid tumors and associated with long progression free disease (P = 0.0004). Furthermore, most tumors with hyperplasia had low World Health Organization or International Federation of Gynecology and Obstetrics grade, had less myometrial invasion, and showed expression of estrogen receptors. All MSI tumors were diploid and had a significantly higher rate of PTEN mutations, but similar rates of KRAS, beta-catenin, and TP53 mutations compared with microsatellite stable tumors. TP53 mutations more often were found in nondiploid tumors but never in tumors with PTEN, KRAS, or beta-catenin mutations, and all PTEN mutations occurred in diploid tumors. CONCLUSIONS. Thus, PTEN, KRAS, beta-catenin, and TP53 mutations occurred in tumors both with and without hyperplasia, but PTEN and TP53 mutations were more common in tumors without hyperplasia. However, none of these genes seems to clearly distinguish tumors with and without hyperplasia, suggesting that other factors may be involved. Conversely, alterations in the PTEN and TP53 genes seem to define distinct subgroups of endometrial carcinoma, the former associated with diploidy and MSI, the latter with macroscopic chromosomal instability.
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| 2. |
- Koul, Anjila, et al.
(författare)
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Identification of TP53 gene mutations in uterine corpus cancer with short follow-up
- 1997
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 1095-6859 .- 0090-8258. ; 67:3, s. 295-302
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Tidskriftsartikel (refereegranskat)abstract
- The involvement of the TP53 tumor suppressor gene in uterine corpus cancer was investigated by single-stranded conformation polymorphism and sequence analysis of its exons 4 to 10. Mutations were found in 12 (18.5%) of 65 cases. Ten of these 12 were single-base substitutions (8 missense and 2 nonsense mutations), whereas 2 were frame-shifting mutations. TP53 gene mutations correlated significantly with advanced surgical stage of disease (P = 0.006) and unfavorable tumor histology types (P = 0.003), whereas the association to myometrial wall invasion did not reach statistical significance (P = 0.054). TP53 gene mutations also correlated significantly with allelic loss at TP53 locus (P = 0.024), absence of estrogen (P = 0.045) and progesterone receptors (P = 0.001), DNA nondiploidy (P = 0.002), and high S-phase fraction values (P = 0.002). Our results suggest that inactivation of the TP53 checkpoint function is associated with disease transition into a stage of rapid progression and spread.
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| 3. |
- Koul, Anjila
(författare)
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Molecular Genetic Alterations In Endometrial And Ovarian Cancers
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Endometrial cancer is the most common gynecological cancer diagnosed in western countries. Complex atypical hyperplasia (CAH) reflects a state of hyperestrinism and its role as a precursor lesion of this cancer is established. Endometrial cancers arising in association with CAH are reported in women of younger age, with early stage disease, favorable histological types, higher progesterone receptor levels and clinically better survival prognosis. However, the molecular events delineated in these two pathogenetic types are less known. Hereditary nonpolyposis colon cancer is caused by germline mutations in DNA mismatch repair (MMR) genes, and associated mainly with cancer in the colon, while endometrial and ovarian cancer are the most common extracolonic malignancies in these patients. Tumors from mutation carriers are characterized by an microsatellite instability (MSI) phenotype, and a subset of sporadic colon cancer demonstrates MSI and somatic mutations in MMR genes. MSI is also reported in a subset of sporadic endometrial cancers, although without identifiable mutation in MMR genes. In this study, endometrial cancers histologically checked for presence/absence of CAH were analyzed for mutations in the TP53, PTEN, KRAS, B-catenin, CDKN2A, BRCA1, and BRCA2 genes, as well as for their DNA ploidy and MSI. Two thirds of the endometrial tumors included in the study contained mutation in either of the seven genes analyzed, but very few cases with coexisting mutations were recorded, suggesting alternate genetic pathways in tumorigenesis. We found that PTEN, KRAS, B-catenin, and TP53 mutations were present in tumors both with and without CAH. PTEN mutations associated with MSI and DNA diploidy, while TP53 mutations related to DNA nondiploidy. Approximately 90% of all endometrial cancers are diagnosed in surgical stage disease I and II, with a five-year survival of 85% to 70%, respectively. A consensus opinion regarding useful prognostic markers to identify a “high-risk” subset among these patients is, however, lacking. In this study, TP53 alterations (mutation or protein overexpression) correlated to several clinicopathological markers of poor prognosis in endometrial cancer, and decreased progression-free survival in both early and advanced stage disease. However, DNA nondiploidy seemed to be an even better marker of poor prognosis in patients with early stage disease (I-II). The strongest risk factor for ovarian cancer is a positive family history of ovarian or breast cancer. While the majority of familial cases are associated with germline BRCA1 or BRCA2 mutation, the frequency of mutations in cases unselected for family history is still unclear. In the present pilot study of ovarian tumors, we detected a surprisingly high frequency of both germline and somatic BRCA-gene mutations, emphasizing the importance of extended analysis of population-based series of patients to determine the true contribution of these predisposing genes to the overall incidence of ovarian cancer in this population. BRCA-gene mutations strongly associated with a serous/seropapillary histological type. Unexpectedly, BRCA1 mutations were seen in two cases of ovarian cancer with brain metastasis.
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| 4. |
- Koul, Anjila, et al.
(författare)
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Prophylactic 3-hour graduated infusion schedule minimizes risk of carboplatin hypersensitivity reactions - A prospective study
- 2018
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258. ; 148:2, s. 363-367
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Aim of this study was observation of hypersensitivity reaction (HSR) frequency by using a 3-hour graduated infusion protocol with appropriate premedication as a prophylactic measure in patients with gynecological cancer receiving carboplatin retreatment in second line or above. None of the patients had experienced HSRs to platinum previously. Method: All the patients in this study received premedication with corticosteroids and anti-histamines followed by carboplatin as 3-hour graduated infusion. Carboplatin was administered either as monotherapy or in combination with other chemotherapeutic agents. Results: Ninety-nine patients with ovarian (n = 71), fallopian tube (n = 9), peritoneal (n = 9) and other gynecological cancers (5 uterine cancer, 5 abdominal cancer of gynecological origin) were retreated by a total of 611. cycles of carboplatin administered as monotherapy (210. cycles) or combination regime (401. cycles). HSRs were recorded in only 11. cycles (1.8%) in a total of 11 patients. While 8 of these patients had grade 1or 2 reactions (8.1%), only 3 patients had grade 3 reactions (3%). After pause in the infusion and complete resolution of HSR symptoms, an attempt of retreatment using this infusion protocol with extra premedication was successful in 6 of these patients without any reoccurrence of HSRs. Conclusion: In this prospective study, we report that prophylactic 3-hour graduated infusion rate with appropriate premedication is associated with low frequency of HSRs in gynecological cancer patients requiring carboplatin retreatment in second line or above.
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| 5. |
- Koul, Anjila, et al.
(författare)
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TP53 protein expression analysis by luminometric immunoassay in comparison with gene mutation status and prognostic factors in early stage endometrial cancer
- 2002
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Ingår i: International Journal of Gynecological Cancer. - : BMJ. - 1048-891X .- 1525-1438. ; 12:4, s. 362-371
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the TP53 tumor suppressor gene have been shown to significantly correlate with poor prognosis in endometrial cancer. In the present study we have evaluated a luminometric immunoassay (LIA) for quantitative estimation of TP53 protein expression in 65 cytosol preparations from endometrial cancer, previously analyzed for mutations in TP53 exons 4-10. LIA showed high (greater than or equal to 0.6 ng/mg protein) expression of TP53 protein in all eight tumors with missense mutation, but high protein levels were also detected in 15 tumors with normal TP53 sequence. All four tumors with nonsense or frameshift mutations had low or no TP53 protein expression. LIA was further evaluated in a retrospective study of 201 cytosol samples from endometrial cancer. TP53 overexpression (>= 0.6 ng/mg protein) was observed in 22% of the tumors and correlated with nonendometrioid histology types (P = 0.005), poorly differentiated tumors (P = 0.001), higher FIGO grade (P = 0.001), DNA nondiploidy (P = 0.002), and high S-phase fraction (P = 0.03). After a median follow-up time of 6.8 years (range 0.7-9.9 years), 22 (13%) progressions were observed in the 175 patients with early stage (I-II) disease. TP53 overexpression (P = 0.04), FIGO grade 3 vs. 1 + 2 (P = 0.01), higher age (P = 0.02), and DNA nondiploidy (P < 0.001) showed significant correlation to shorter progression-free survival in these patients. We conclude that TP53 protein analysis by LIA provides an incomplete correlation to mutation status and cannot substitute for mutation analysis in assessment of prognosis in endometrial carcinoma. In comparison to TP53 overexpression and higher FIGO grades, DNA nonploidy status seems to be a better prognostic indicator to define a subset of early stage endometrial cancer patients who may benefit by adjuvant chemotherapy/radiotherapy.
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| 6. |
- Koul, Anjila, et al.
(författare)
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Two BRCA1-positive epithelial ovarian tumors with metastases to the central nervous system: a case report
- 2001
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 1095-6859 .- 0090-8258. ; 80:3, s. 399-402
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cerebral metastasis secondary to ovarian cancer is a rare phenomenon. While no clear relationship to known prognostic factors is found, others suggest this as a biologically diverse behavior of ovarian cancer. CASES: In a pilot study, 37 invasive epithelial ovarian cancer samples were analyzed to detect the frequency of BRCA1/BRCA2 mutations in the south of Sweden (results published). A retrospective follow-up revealed that 2 of these (2/37; 5.4%) patients developed central nervous system metastases during the course of their disease. Both patients had advanced surgical stage disease at the time of diagnosis, with histopathological serous type tumors that were negative for estrogen and progesterone receptors. One of these patients carried a germline BRCA1 mutation, whereas a somatic BRCA1 mutation was identified in the other patient. CONCLUSIONS: To the best of our knowledge the molecular genetic profile of these tumors is not found in the literature and it is suggested that such analyses could provide some insight for a better understanding of this rare phenomenon.
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