Somatic D-loop mitochondrial DNA mutations are frequent in uterine serous carcinoma

Pejović, Tanja; Ladner, Daniela P.; Intengan, Marilyn; Zheng, Karl; Fairchild, Tracy; Easley, Samantha; Dillon, Dionne; Marchetti, David L.; Schwartz, Peter E.; Lele, Shashikant; Costa, José; Odunsi, Kunle

doi:10.1016/j.ejca.2004.07.009

Cited by 24 publications

(22 citation statements)

References 20 publications

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“…One out of six (16%) endometrial carcinomas showed mutations of the D310 mitochondrial mononucleotide repeat (34). In the current study, somatic mtDNA mutations were reported only in 10% (4 out of 40) of primary ECs, a frequency significantly lower compared with the data reported previously [25% by Liu et al (31) or 63% by Pejovic et al (15)]. However, only approximately 10% of mtDNA were screened for the molecular genetic alterations in human ECs, and we suggest that the frequency of mtDNA alterations would be higher when complete sequence analysis of the mtDNA genome would be performed.…”

Section: Discussioncontrasting

confidence: 53%

“…Liu et al (14) detected a high (60%) incidence of mtDNA mutations by sequencing DNAs isolated from malignant ovarian tissues. Somatic D-loop mitochondrial DNA mutations were detected at high frequency in uterine serous carcinomas extracted from paraffin-embedded slides (15). Moreover, Wang et al (16) reported that about 25.4% of cervical carcinomas, 48.4% of endometrial cancers, and 21.9% of ovarian carcinomas carried one or more mtMSI.…”

Section: Introductionmentioning

confidence: 99%

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Clinicoprognostical features of endometrial cancer patients with somatic mtDNA mutations

Semczuk¹,

Lorenc²,

Putowski³

et al. 2006

Oncol Rep

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Abstract. Somatic mitochondrial DNA (mtDNA) mutations have been found in a subset of endometrial cancers (EC) from different populations. We have investigated the relationship between mtDNA changes and clinical and pathological variables of women affected by EC. mtDNA mutations were detected both in early (3/32; 9%) and in advanced (1/8; 12%) stages of uterine tumors. However, patients carrying the mtDNA mutations or the normal mtDNA sequence had indistinguishable clinicopathological data, including age, clinical stage, histological grade and type or depth of myometrial invasion. It is noteworthy that mtDNA mutations were not detected in hyperplastic endometrial tissues or in ECs coexisting with hyperplasia, nor in a single case of endometrial stromal sarcoma. LOH at the tumor suppressor genes RB1 and TP53 as well as p16 INK4A alterations (LOH, gene deletion) were found in tumors carrying mtDNA mutations. These results suggest that somatic mtDNA mutations are detected in a subset of ECs, although they are unrelated to clinicopathological variables of cancer. IntroductionEndometrial cancer is one of the most frequently occurring gynecological malignancies in the Western World, and its incidence has increased significantly during the last decade in Poland (1). In general, clinicopathological, immunohistochemical, biochemical and molecular genetic analyses have provided valuable information for dividing ECs into two different subtypes, estrogen-dependent (type I) and estrogenindependent (type II) (2-4). Factors associated with unopposed estrogenic stimulation and the presence of hyperplastic endometrial lesions (concomitant with neoplasia) are linked with the most common type of carcinoma, endometrioid-type I tumor (5-6). On the other hand, USC and clear cell carcinoma of the endometrium, which are not linked to estrogenic stimulation and are not associated with endometrial hyperplasia, are considered type II tumors (5,6). These sub-types differ not only in clinicoprognostical features but also in various molecular genetic alterations detected in oncogenes, tumor suppressor genes and mismatch-repair genes (5). For example, pRb1-cyclin D1-cdk4/6-p16 INK4A pathway alterations were described in endometrioid-type ECs whereas they were uncommon in USCs in humans (7).Mitochondria play important roles in cell homeostasis, actively participating in energy metabolism, generation of reactive oxygen species, aging and initiation of programmed cell death (8,9). Mitochondrial failure has been described at all levels of structure and function, including abnormal ultrastructure, metabolic deregulation and genetic alterations (10). In general, mtDNA point mutations, gene deletions and mtMSI have been reported in human neoplasms and cell lines, but the frequency of these alterations differs in various tumors (11-13). The most well-known disorders caused by mtDNA mutations are LHON (Leber's Hereditary Optic Neuropathy), MELAS (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes), MERRF (Myoclonic Epilepsy with Rag...

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Section: Discussioncontrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Clinicoprognostical features of endometrial cancer patients with somatic mtDNA mutations

Semczuk¹,

Lorenc²,

Putowski³

et al. 2006

Oncol Rep

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“…If the DNA sequence in the tumor mtDNA differed from the matched PBMC mtDNA, this was defined as a somatic mutation. 21 Likewise, if the mtDNA sequence in irradiated cells differed from nonirradiated cells, this was defined as a mutation.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial DNA somatic mutations are frequent in nasopharyngeal carcinoma

Pang

Shao²,

Xiao³

et al. 2008

Cancer Biology & Therapy

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“…Recently, a high incidence of specific mtDNA alterations has been reported for gastric (Maximo et al, 2001;Wu et al, 2005), prostate (Jeronimo et al, 2001;Petros et al, 2005), pancreatic (Jones et al, 2001), skin (Girald-Rosa et al, 2005), colorectal (Polyak et al, 1998;Hibi et al, 2001a;Lievre et al, 2005), urinary bladder (Fliss et al, 2000), thyroid (Yeh et al, 2000), oesophageal (Hibi et al, 2001b;Kumimoto et al, 2004), liver (Nishikawa et al, 2001), breast (Richard et al, 2000;Tan et al, 2002;Zhu et al, 2005), uterine cancers (Pejovic et al, 2004) as well as chromophobe renal cell carcinoma (Nagy et al, 2002). Of all mtDNA mutations reported in cancer tissues, only a few are known to be of pathological relevance as shown for patients with disorders of the mitochondrial energy metabolism.…”

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confidence: 99%

Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism

et al. 2006

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Previously, renal cell carcinoma tissues were reported to display a marked reduction of components of the respiratory chain. To elucidate a possible relationship between tumourigenesis and alterations of oxidative phosphorylation, we screened for mutations of the mitochondrial DNA (mtDNA) in renal carcinoma tissues and patient-matched normal kidney cortex. Seven of the 15 samples investigated revealed at least one somatic heteroplasmic mutation as determined by denaturating HPLC analysis (DHPLC). No homoplasmic somatic mutations were observed. Actually, half of the mutations presented a level of heteroplasmy below 25%, which could be easily overlooked by automated sequence analysis. The somatic mutations included four known D-loop mutations, four so far unreported mutations in ribosomal genes, one synonymous change in the ND4 gene and four nonsynonymous base changes in the ND2, COI, ND5 and ND4L genes. One renal cell carcinoma tissue showed a somatic A3243G mutation, which is a known frequent cause of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episode) and specific compensatory alterations of enzyme activities of the respiratory chain in the tumour tissue. No difference between histopathology and clinical progression compared to the other tumour tissues was observed. In conclusion, the low abundance as well as the frequently observed low level of heteroplasmy of somatic mtDNA mutations indicates that the decreased aerobic energy capacity in tumour tissue seems to be mediated by a general nuclear regulated mechanism.

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Somatic D-loop mitochondrial DNA mutations are frequent in uterine serous carcinoma

Cited by 24 publications

References 20 publications

Clinicoprognostical features of endometrial cancer patients with somatic mtDNA mutations

Clinicoprognostical features of endometrial cancer patients with somatic mtDNA mutations

Mitochondrial DNA somatic mutations are frequent in nasopharyngeal carcinoma

Mitochondrial DNA mutations in renal cell carcinomas revealed no general impact on energy metabolism

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