Risk of gynecologic cancers in Danish hereditary non‐polyposis colorectal cancer families

Boilesen, Astrid E. B.; Bisgaard, Marie Luise; Bernstein, Inge

doi:10.1080/00016340802443806

Cited by 23 publications

(13 citation statements)

References 24 publications

(36 reference statements)

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“…The highest estimated lifetime risk is 12% 1. Other reports present an estimate between 4% and 8% 2 3. According to Watson et al lifetime risk is higher in carriers of MSH2 mutations than in carriers of MLH1 mutations 2.…”

mentioning

confidence: 97%

Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds

Grindedal

Renkonen–Sinisalo

Vasen

et al. 2009

Journal of Medical Genetics

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confidence: 97%

Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds

Grindedal

Renkonen–Sinisalo

Vasen

et al. 2009

Journal of Medical Genetics

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“…The frequency increases to 6%-10% in women younger than 50 years (6,7). Of women with Lynch syndrome, 8%-12% develop epithelial ovarian tumors in their lifetime (8)(9)(10), with higher risks in those with hMSH2 or hMSH6 mutation (10,11). Identifying epithelial ovarian tumors with MMR defects is not only important for early detection of women with Lynch syndrome, but may also have treatment implications.…”

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confidence: 99%

Prevalence of Loss of Expression of DNA Mismatch Repair Proteins in Primary Epithelial Ovarian Tumors

Gilks

Mulligan

et al. 2012

International Journal of Gynecological Pathology

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Although different histologic subtypes of epithelial ovarian tumors have long been recognized, their molecular abnormalities have not been fully defined. We examined the prevalence of DNA mismatch repair (MMR) protein loss in these tumors. Tissue microarrays (TMA) of suspected ovarian carcinomas were stained for hMLH1, hMSH2, hMSH6, and hPMS2 and scored separately by 2 groups of investigators. Loss of staining (negative) or discrepant staining results on TMA were verified on whole-section slides. Intact (positive) staining results were also verified for an additional 25 randomly selected cases. Clinical data for cases demonstrating MMR protein loss were collected. A second set of TMA composed purely of mucinous tumors was also stained for antibodies to MMR proteins and scored by 1 group of investigators. TMA was an effective method for screening a large number of ovarian tumors for MMR protein expression, with a sensitivity of 100% for all 4 MMR proteins, and a specificity of 22.2%-53.8% for different MMR proteins. Of the primary epithelial tumors of the ovary, loss of expression of MMR proteins was significantly more common in the endometriosis-associated carcinomas (7/69; 10.1%) than in high-grade serous carcinomas (2/182; 1.1%): P=0.0021. The former group also showed more frequent loss of MMR proteins compared with mucinous intestinal-type carcinomas (0/32; P=0.0940). Cases within the group of endometriosis-associated carcinomas were endometrioid (2/29 cases), clear cell (1/27 cases), undifferentiated (1/8 cases), and mixed carcinomas with an endometrioid, clear cell, and/or undifferentiated component (3/5 cases). No loss of MMR protein expression was identified in epithelial tumors of other histologic subtypes. Our study demonstrated the loss of MMR protein expression in 10.1% of endometriosis-associated ovarian carcinomas. These results raise the possibility of selective screening for Lynch syndrome in patients with these types of ovarian carcinoma.

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“…Possible reasons for a change in EC risk after colorectal cancer diagnosis include, but are not limited to: effects of radio‐ or chemo‐therapy for the colorectal cancer, increased surveillance, weight change and changes in exposures to environmental risk factors. A number of attempts have been made to address this question, but the relationship could not be estimated with sufficient precision due to the limited number of cases analyzed or the design of the original study 10–12. If women with Lynch syndrome‐related colorectal cancer have an increased risk for subsequent primary gynecological cancer, they could be advised to undertake interventions such as screening13, 14 and/or risk‐reducing surgery to prevent subsequent primary cancers.…”

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confidence: 99%

Risk of endometrial cancer for women diagnosed with HNPCC‐related colorectal carcinoma

Obermair

Youlden

Young

et al. 2010

Intl Journal of Cancer

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The risk of endometrial cancer (EC) subsequent to a diagnosis of colorectal cancer in women with a germline mutation in a mismatch repair gene [Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC)] is unknown. We estimated the risk of EC following a diagnosis of colorectal carcinoma (CRC) for women with Lynch syndrome. A retrospective cohort study was performed on women diagnosed with CRC with a germline mutation in a mismatch repair (MMR) gene (Lynch syndrome cases), and women with microsatellite stable (MSS) CRC who were not known to carry a germline mutation (non-Lynch cases), identified from the Colon Cancer Family Registry. The incidence of EC following CRC was estimated and compared for women with and without Lynch syndrome, using adjusted hazards ratios calculated for time at risk among each group. A total of 112 women with Lynch syndrome and a previous diagnosis of CRC were compared with 908 women without Lynch and with a MSS CRC diagnosis. The estimated 10-year cumulative risk of EC subsequent to CRC was 23.4% [95% confidence interval (CI): 15-36%] for Lynch syndrome women compared with 1.6% (95% CI: 0.7-3.8%) for non-Lynch women. After adjusting for ascertainment, age at diagnosis and diagnosis of other cancers, risk of subsequent diagnosis with EC was elevated sixfold in women with Lynch syndrome compared with non-Lynch women (HR 6.2; 95% CI 2.2-17.3; p 5 0.001). Approximately one quarter of women diagnosed with Lynch syndrome-associated CRC developed EC within 10 years. This supports the sentinel cancer concept and suggests that active and early management is important for these women.Lynch syndrome [also known as hereditary non-polyposis colon cancer (HNPCC)] is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6 or PMS2. Carriers of MMR gene mutations are at increased risk of cancers of the colon, endometrium, ovary, upper urologic tract, stomach, small bowel, biliary/pancreas, skin and brain. 1 In individuals who carry such mutations, inactivation of the remaining normal allele in a cell results in dysfunctional or absent DNA MMR. These unrepaired mismatches typically occur in regions of repetitive nucleotide sequences, commonly referred to as microsatellites. The consequent phenotype, referred to as microsatellite instability (MSI), is the signature change in Lynch syndrome-associated cancers. 2,3 Detection of a deleterious germline mutation in a particular MMR gene in a case of cancer with MSI unequivocally establishes the diagnosis of Lynch syndrome, with MLH1 and MSH2 sequence variants accounting for 80% of all MMR gene mutations. 4 Early age of cancer diagnosis and multiplicity of cancers are considered hallmarks of Lynch syndrome. A meta-analysis 5 of data from three population-based studies, 6-8 and previous clinic-based work, 9 estimated that the risk of colorectal cancer for MLH1 and MSH2 carriers to age 70 years was 53% for males, 33% for females and for endometrial cancer (EC) was 44%. Although the increased risk of EC in women wi...

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Risk of gynecologic cancers in Danish hereditary non‐polyposis colorectal cancer families

Cited by 23 publications

References 24 publications

Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds

Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds

Prevalence of Loss of Expression of DNA Mismatch Repair Proteins in Primary Epithelial Ovarian Tumors

Risk of endometrial cancer for women diagnosed with HNPCC‐related colorectal carcinoma

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