| 词条 | Draft:PapSEEK |
| 释义 |
{{comment|(non-AfC-reviewer comment)}} I'd recommend making the introduction more accessible to the layman. The introduction should summarize the technique, its sensitivity, and application, like the article on cancer.gov does. I'd recommend blending the section "Limitations" into another section in a more summarized prose. Is PapSEEK a trademark? The article seems to be about a single retrospective study (a primary source), so maybe it would be better to wait for a review article (a secondary source) like MEDRS recommends. – Þjarkur (talk) 20:28, 6 March 2019 (UTC) PapSEEK is an experimental screening test for detecting some endometrial and ovarian cancers.[1] It is based on the sequencing and genetic analyses of DNA obtained from a routine Pap test.[2] Using a multiplex PCR-based test, PapSEEK detects somatic mutations in the 18 most commonly mutated genes in endometrial and ovarian cancers.[2] Assays are also used to detect aneuploidy in samples that may not have mutations in any of the 18 genes.[2] PapSEEK aims to increase sensitivity of cancer screening in two ways: 1. Using a “Tao brush” that allows for collection of samples that are anatomically closer to the sites of the tumor.[2] 2. Combine Pap test fluid sample analysis with plasma analysis results.[2] The outcome of PapSEEK demonstrates an increased detection of early stage gynecological cancers using mutation-based diagnostics.[2] HistoryThe Pap test is highly valuable for early detection of cervical cancers through screening of populations and reducing the mortality rate of people with cervical cancer. However, the Pap test can only detect cervical cancer and not other gynecological cancers such as endometrial and ovarian cancers.[3][4][5] Due to this discrepancy, the most lethal gynecological cancers in countries where Pap test is routinely performed are endometrial and ovarian cancers[6] Together, these two cancers are the third-leading cause of cancer mortality in women and account for approximately 25,000 deaths each year in the United States.[6] Currently, the most diagnostic test used for detecting endometrial cancer is the Transvaginal Ultrasound (TVUS).[2] TVUS measures the thickness of the endometrium, however it is limited in its ability to differentiate between malignant and benign tumors.[2] This limitation often leads to unnecessary invasive procedures on women without cancer. In addition, only 1 in every 50 women tested positive for TVUS actually do have endometrial cancer, indicating a high false-positive rate.[2] Ovarian cancer is even more difficult to detect and often diagnosed at a later stage, leading to a high mortality rate.[6] Screening the general population for ovarian cancers with the current diagnostic approaches, including TVUS, results in unnecessary invasive interventions that are not recommended.[2] One of the most common ovarian cancers with the lowest survival rates is high-grade serous carcinoma (HGSC).[2] Recently, more evidence supports the fact that HGSC is initiated in the fallopian tube and migrates to the ovarian surface for implantation.[7][8][9][10] Moreover, a recent study suggests that most early-stage HGSCs originate in extraovarian sites.[11] This may be a possible explanation for the low sensitivity of TVUS when detecting early-stage ovarian cancer since no ovarian abnormalities are present at this stage.[2] Thus, developing an effective screening test as a diagnostic approach for these cancers is of high priority. PapSEEK can help overcome the barriers in routine screening tests by detecting tumor cells that are shed into the vaginal tract and/or the uterine cavity of women with ovarian and endometrial cancers.[2] ProcedureA regular Papanicolaou (Pap) test is first performed to collect cells from the cervical opening (cervical os)[12]. DNA recovered is then amplified to detect for mutations in 18 genes as well as aneuploidy[12][13][14]. Detection of somatic mutationsA multiplex PCR-based approach is used to detect mutations commonly found in endometrial and ovarian cancers.[2] 139 primers were designed to amplify distinct regions within the 18 genes of interest: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, KRAS, MAPK1, NRAS, PIK3CA, PIK3R1, POLE, PPP2R1A, PTEN, RNF43, and TP53.[12][13][14] Each amplification segment is about 110- to 142-bp in length, covering a total of 9392 nucleotides in the DNA.[2] Three multiplex PCRs with non-overlapping amplicons were performed for each sample.[2] To capture the minor fraction of neoplasm DNA within the Pap smear sample, a PCR-based error-reduction technology ‘Safe-Sequencing System (Safe-SeqS)’ is used to amplify the DNA.[15] One primer from each primer pair contains a 14-nt unique molecular identifier (UMI).[2] Hence, amplified DNA segments containing the same UMI are seen as segments originating from a common template. In this way, rare mutations can be amplified and detected without being affected by PCR-bias. Detection of aneuploidyIn addition to somatic mutation analysis, PapSEEK also evaluates sample aneuploidy to spot cancers with no mutation in any of the 18 genes assessed.[2] An amplicon-based approach is employed to detect aneuploidy.[16] In each sample, a single primer pair is used to amplify ~38,000 loci of long interspersed nucleotide elements (LINES) throughout the genome.[16] LINEs are dispersed widely on all chromosomes, making it a great primer binding sequence to detect gains and losses of chromosome arms. Amplified segments are then sequenced by the Illumina platform.[2] Data obtained are processed using the Within-Sample AneupLoidy DetectiOn (WALDO) software.[17] WALDO uses supervised machine learning to categorize aneuploid and euploid samples.[17] Samples having a support vector machine (SVM) score above a given threshold are classified as aneuploid. Samples having a gain of chromosome arm 7q and 8q, which are often gained in ovarian and endometrial cancers,[18][19] are also recognized as aneuploid by the software.[2] Combining the detection for somatic mutations and aneuploidy, PapSEEK screens Pap brush and Tao brush samples for endometrial and ovarian cancers. A sample is reported positive if it contains either a mutation or a gain or loss in chromosome arm.[2] Tao brush vs Pap brushOne possible way to improve PapSEEK’s sensitivity is to collect cells from the intrauterine cavity (compared to the endocervical canal in regular Pap test).[2] Tao brush IUMC Endometrial Sampler (Tao brush), rather than Pap brush, is used for this purpose[20]. Tao brush is a Food and Drug Administration (FDA)-approved tool for endometrial sampling without the need for anesthesia.[2] The brush is equipped with a retractable outer sheath that cover the brush completely during insertion and removal, preventing injury to the myometrium and contamination from endocervix and vagina.[20] During intrauterine sampling, Tao brush is gently inserted to the level of uterine fundus. The outer sheath is then pulled back to allow direct contact of the brush with the endometrium. Then, the brush is rotated 360° clockwise and then counterclockwise to collect tissue sample. The sheath is then replaced, and the device is removed.[20] DNA recovered from tissues collected is then analysed for somatic mutations and aneuploidy. PapSEEK in plasmaAnother way to improve PapSEEK’s sensitivity is to assess mutations in both Pap test sample and plasma sample. Tumor cells shed free DNA called "circulating tumor DNA (ctDNA)" into peripheral blood.[21] Collecting plasma samples can prevent contamination from cells, and thus plasma has been proven to be a superior source of ctDNA.[22] After DNA recovery from plasma samples, 61 primer pairs are used to amplify regions located within 16 genes of interest: AKT1, APC, BRAF, CDKN2A, CTNNB1, EGFR, FBXW7, FGFR2, GNAS, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53.[23] ctDNA is often degraded and have a smaller size, thus primers are designed to amplify a shorter DNA fragment within 67- to 81-base pair(bp).[2] Mutation detection is followed by standard PapSEEK analysis. SensitivityUsing the PapSEEK technique with the Pap brush samples from 382 endometrial cancer patients, 81% of these patients tested positive.[2] Out of the patients who tested positive, 78% had early-stage disease, indicating the value of this diagnostic test for early detection of endometrial cancer.[2] For ovarian cancer, 33% of the 245 patients tested positive using the Pap brush sample and only 34% of the patients who tested positive had early-stage disease.[2] Despite this low sensitivity for ovarian cancer, the specificity for PapSEEK using Pap brush samples was reasonably high with only 1.4% of the 714 women without cancer who tested positive.[2] The Tao brush sampling however, displayed an increased endometrial and ovarian cancer detection than Pap brush samples.[2] Out of the 123 endometrial cancer patient samples collected using Tao brush, 93% tested positive, indicating high sensitivity. In addition, 45% of the 51 patients with ovarian cancers tested positive.[2] The Tao brush also had 100% specificity with no patients testing positive out of 125 women without cancer.[2] Lastly, sensitivity was evaluated for PapSEEK analysis with plasma collection in patients with ovarian cancer. Plasma was collected from 83 ovarian cancer patients and 43% of these patients had circulating tumor DNA.[2] The combination of Pap brush samples and plasma collection increased the sensitivity to 63% of the 83 patients with ovarian cancer.[2] ApplicationPapSEEK is an economical, non-invasive test capable of detecting some endometrial and ovarian cancers at their early-stages.[2] Currently, TVUS and serum CA 125 test are used to detect and monitor endometrial and ovarian cancers. However, both tests have limitations: TVUS is unable to discriminate malignant and benign tumors; CA 125 serum is also present in a series of common benign conditions. Currently PapSEEK is still being tested only in a retrospective study but it may one day be incorporated into clinical use. PCR-based mutation detection can also be used for screening other cancers. UroSEEK has been suggested to detect bladder cancer and upper tract urothelial cancer using DNA recovered from cells shed into urine.[24] Another liquid biopsy test, CancerSEEK, helps identify eight different tumors by screening blood samples for a combination of genetic mutations and protein biomarkers.[25] Limitations
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