Wednesday, October 26, 2016
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population
abstract
Lynch syndrome caused by constitutional mismatch‑repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.
[Clinicopathologic characteristics and prognosis of upper tract urothelial carcinoma: an analysis of 368 radical nephroureterectomy specimens].
abstract: (China)
[Clinicopathologic characteristics and prognosis of upper tract urothelial carcinoma: an analysis of 368 radical nephroureterectomy specimens].
Conclusions: Chinese UTUC reveals its unique epidemiology. UTUC more commonly occurs in women and has a similar incidence between the renal pelvic and ureteral carcinoma. Patients with history of renal transplantation are prone to detect UTUC through physical examination rather than hematuria.....
Differences in survival for patients with familial and sporadic cancer.
abstract
Family history of cancer is a well-known risk factor but the role of family history in survival is less clear. The aim of this study was to investigate the association between family history and cancer survival for the common cancers in Sweden. Using the Swedish population-based registers, patients diagnosed with the most common cancers were followed for cancer-specific death during 1991-2010. We used multivariate proportional hazards (Cox) regression models to contrast the survival of patients with a family history of cancer (individuals whose parent or sibling had a concordant cancer) to the survival of patients without a family history. Family history of cancer had a modest protective effect on survival for breast cancer (hazard ratio (HR) = 0.88) and prostate cancer (HR = 0.82). In contrast, family history of cancer was associated with worse survival for nervous system cancers (HR = 1.24) and ovarian cancer (HR = 1.20). Furthermore, the poorer survival for ovarian cancer was consistent with a higher FIGO stage and a greater proportion of more aggressive tumors of the serous type. The better survival for patients with a family history of breast and prostate cancer may be due to medical surveillance of family members. The poor survival for ovarian cancer patients with an affected mother or sister is multifactorial, suggesting that these cancers are more aggressive than their sporadic counterparts.
open access: Cutaneous metastases from adenocarcinoma of the ovary (breast cancer rash...)
open access - case report/review
Case report
A 24-year-old Hispanic woman presented with a 3-month history of painful, pruritic, progressive rash localized to both breasts. Her medical history was significant for refractory metastatic stage IIIB mucinous adenocarcinoma of the ovary diagnosed 10 months before appearance of the rash..... The patient was discharged home to hospice care and died 4 months after appearance of the rash.Discussion
Cutaneous metastasis is an uncommon manifestation of internal malignancy. Spread of a primary tumor to the skin typically occurs late in the course of disease but may be the presenting sign of underlying cancer.....Our case is one example of the many unusual presentations of cutaneous metastatic ovarian cancer.
CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis
abstract
Ovarian clear cell carcinoma is a unique type of ovarian cancer, often derived from endometriosis, and advanced-stage disease has a dismal prognosis primarily due to the resistance to conventional chemotherapy. Previous studies have shown frequent somatic mutations in ARID1A, PIK3CA, hTERT promoter, and amplification of ZNF217; however, the molecular alterations that are associated with its aggressiveness remain largely unknown. This study examined and compared cyclin E1 expression in endometriosis-related ovarian tumors, with the aim of determining the relationship between hTERT mutations and ARID1A expression and evaluating the effects of these molecular alterations on patient survival. We performed immunohistochemistry on 207 tumors [clear cell carcinoma (n=120), endometrioid carcinoma (n=49), and seromucinous tumors (n=38)], followed by two-color fluorescence in situ hybridization (n=88) and compared with ARID1A expression and hTERT promoter mutations in the same samples. Cyclin E1 overexpression and CCNE1 copy-number gain occurred in 23.3% and 14.8% of ovarian clear cell carcinomas, respectively, but they were not detected in any of the other endometriosis-related tumors. All cases with CCNE1 copy-number gain demonstrated an intense cyclin E1 immunoreactivity (P<0.001). Cyclin E1 overexpression was positively correlated with hTERT promoter mutations (P=0.01), but not with the loss of ARID1A expression. A multivariate analysis revealed that CCNE1 overexpression predicts poor overall survival, even after adjusting for stage and age. Specifically, CCNE1 overexpression and copy-number gain were both correlated with a poor outcome in patients with stage I disease. Moreover, the subset with CCNE1 overexpression and ARID1A retention demonstrated the worst outcome. Our findings suggest that gene copy-number gain and upregulation of CCNE1 occur in ovarian clear cell carcinoma and are associated with a worse clinical outcome, dictating the survival of early-stage patients, and that these molecular alterations are unique to clear cell carcinoma among different types of endometriosis-related ovarian neoplasms.Modern Pathology
Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Screening - changes Oct 21st
Overview
Note: Separate PDQ summaries on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention; Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment; Ovarian Germ Cell Tumor Treatment; and Ovarian Low
Malignant Potential Tumor Treatment are also available.
Evidence of Lack of Mortality Benefit Associated with Screening
Single-threshold cancer antigen 125 (CA-125) levels and transvaginal ultrasound (TVU)
There is solid evidence to indicate
that screening women aged 55 to 74 years at average risk of developing
ovarian cancer with the serum marker CA-125 (at a fixed threshold for a
positive result of 35 U/mL) annually for 6 years and TVU for 4 years
does not result in a decrease in ovarian cancer mortality, after a
median follow-up of 14.7 years.
Magnitude of Effect: The ovarian cancer mortality rate
was 3.8 deaths per 10,000 women in the screened group and 3.6 deaths per
10,000 person-years in the usual-care group, yielding a mortality rate
ratio of 1.06 (95% confidence interval [CI], 0.87–1.30).[1]
- Study Design: Evidence obtained from one randomized controlled trial.
- Internal Validity: Good.
- Consistency: One trial has evaluated the impact on mortality from ovarian cancer.
- External Validity: Good.
Screening with TVU alone or with multimodal screening with CA-125 levels, assessed using the Risk of Ovarian Cancer Algorithm (ROCA), with TVU
Screening with TVU alone or with
multimodal screening with CA-125 levels, assessed using the ROCA,
combined with TVU in the United Kingdom Collaborative Trial of Ovarian
Cancer Screening (UKCTOCS) did not show a mortality benefit of screening
with either approach based on a predetermined primary endpoint among
women undergoing 7 to 11 screens and a median of 11.1 years of
follow-up.[2]
Magnitude of Effect: Multimodal screening was associated
with a nonsignificantly lower mortality than with no screening (15%
lower mortality; 95% CI, -3% to 30%; P = .10). Ultrasound only screening also resulted in nonsignificantly lower mortality (11% lower mortality; 95% CI, -7% to 27%; P = .21).[2]
- Screening complications were less than 1% for both TVU only and multimodality screening strategies.
- Study Design: Evidence obtained from one randomized controlled trial.
- Internal Validity: Good.
- Consistency: One trial has evaluated the impact on mortality from ovarian cancer using this specific approach.
- External Validity: Good—based on data from other studies assessing complementary endpoints.
Statement of Harms
Based on solid evidence, screening for
ovarian cancer results in false-positive test results. Screened women
had higher rates of oophorectomy and other minor complications such as
fainting and bruising.
Magnitude of Effect:
- Of screened women, 9.6% had false-positive results, resulting in 6.2% undergoing surgery. The surgical complication rate was 1.2% for all screened women.
- Oophorectomy rates were 85.7 per 10,000 person-years among screened women and 64.2 per 10,000 person-years among usual-care women.
- Minor complications with screening: 58.3 cases per 10,000 women screened with CA-125 and 3.3 cases per 10,000 women screened with transvaginal sonogram (TVS).
- Study Design: Evidence obtained from one randomized controlled trial.
- Internal Validity: Good.
- Consistency: Not applicable (N/A).
- External Validity: Good.
In the TVU-only arm of the UKCTOCS
trial, there were 50 false-positive surgical procedures, and in the
multimodality arm, there were 14 false-positive operations per 10,000
screens.[2]
In the general population, screening is
targeted to postmenopausal women, and the major complications are
related to surgery. Among younger women, the potential target group
among BRCA1/2 mutation carriers, oophorectomy at younger than
45 years may increase mortality secondary to cardiovascular disease.
Oophorectomy, if performed among younger women, may also reduce risk of
estrogen receptor–positive breast cancers, which occur with elevated
frequency among carriers of BRCA2 mutations.
References
- Buys SS, Partridge E, Black A, et al.: Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA 305 (22): 2295-303, 2011. [PUBMED Abstract]
- Jacobs IJ, Menon U, Ryan A, et al.: Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet 387 (10022): 945-56, 2016. [PUBMED Abstract]
- Updated: October 21, 2016
Tuesday, October 25, 2016
Body weight changes in patients undergoing chemotherapy for ovarian cancer influence progression-free and overall survival | SpringerLink
abstract:
Body weight changes in patients undergoing chemotherapy for ovarian cancer influence progression-free and overall survival
Purpose
The
aim of this study was to evaluate whether body weight changes in
patients undergoing chemotherapy for epithelial ovarian cancer (EOC)
influence progression-free survival (PFS) and overall survival (OS).
Methods
An
analysis of 190 patients diagnosed with ovarian cancer after first-line
chemotherapy was conducted. Changes in body weight were assessed by
comparing measurements at baseline to those of the third and sixth
cycles of chemotherapy. PFS and OS were calculated with the Kaplan–Meier
method and multivariate Cox model.
Results
Significant
reduction in body weight in advanced EOC was observed with no changes
in early EOC. Significant differences in PFS were observed in advanced
EOC patients that lost more than 5 % of their body weight (6 months),
maintained weight (13 months), or gained more than 5 % of their body
weight (15 months). Similarly, significant differences in OS were noted
in advanced EOC at the following time points: 24.3, 42.4, and
66.2 months. No effect was reported for early EOC patients. The
multivariate Cox analysis showed significant body weight changes from
the first to the sixth chemotherapy cycle for PFS (HR = 0.97) and OS (HR = 0.94) as well as from the
first to the third chemotherapy cycle for OS (HR = 0.93).
Conclusions
Body
weight changes can be recognized as a prognostic factor for PFS and OS
in advanced EOC patients undergoing chemotherapy. Weight loss is
associated with poorer survival while weight gain improved outcomes.
open access: The epidemiologic status of gynecologic cancer in Thailand
JGO :: Journal of Gynecologic Oncology
Fig. 1.
Top ten cancers in Thailand (female) (estimated), 2011 [4].
2. Ovarian cancer
The mean ovarian cancer incidence per annum is 6.0 per 100,000
females in 2011. Bangkok, Lamphun and Krabi province had the highest
number of incidence comparing to other provinces (ASR=7.3), while the
Northeastern region had the lowest number of new cases of ovarian cancer
(ASR=4.4). The incidence of ovarian cancer increased from the age of 55
years onward. This shows that there is a later onset of the cancer
compared to 1999 where the peak incidence was in the age group 40–65 [2].
The incidence can occur since very young age. Interestingly, the most
common histological types of ovarian cancer in 2011 were serous
carcinoma followed by mucinous carcinoma and endometrioid carcinoma.
This showed a larger variation from the data in 1999 as the two most
prevalent histological types were serous and mucinous cystadenocarcinoma
[2]. The most common stage of ovarian cancer was local, followed by regional stage.
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