Endometrial Cancer and Lynch Syndrome: Clinical and Pathologic Considerations

Meyer, Larissa A.; Broaddus, Russell R.; Lu, Karen H.

doi:10.1177/107327480901600103

Cited by 219 publications

(153 citation statements)

References 41 publications

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“…Furthermore, germline mutations associated with Lynch syndrome has been described in 2-3% of patients diagnosed with endometrial cancer. Among Lynch syndrome-related cancers, endometrial cancer is riskier than colorectal cancer in terms of estimated lifetime cumulative risk (32). The overall 5-year survival rate for endometrial (88 vs. 82%) or ovarian cancer (64 vs. 58%) was not significantly different between patients with endometrial or ovarian cancer that are associated with Lynch syndrome and the controls with sporadic cases (33,34).…”

Section: Lynch Syndromementioning

confidence: 88%

Hereditary breast and ovarian cancer susceptibility genes (Review)

et al. 2013

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Abstract. Women with hereditary breast and ovarian cancer (HBOC) syndrome represent a unique group who are diagnosed at a younger age and result in an increased lifetime risk for developing breast, ovarian and other cancers. This review integrates recent progress and insights into the molecular basis that underlie the HBOC syndrome. A review of English language literature was performed by searching MEDLINE published between January 1994 and October 2012. Mutations and common sequence variants in the BRCA1 and BRCA2 (BRCA) genes are responsible for the majority of HBOC syndrome. Lifetime cancer risks in BRCA mutation carriers are 60-80% for breast cancer and 20-40% for ovarian cancer. Mutations in BRCA genes cannot account for all cases of HBOC, indicating that the remaining cases can be attributed to the involvement of constitutive epimutations or other cancer susceptibility genes, which include Fanconi anemia (FA) cluster (FANCD2, FANCA and FANCC), mismatch repair (MMR) cluster (MLH1, MSH2, PMS1, PMS2 and MSH6), DNA repair cluster (ATM, ATR and CHK1/2), and tumor suppressor cluster (TP53, SKT11 and PTEN). Sporadic breast cancers with TP53 mutations or epigenetic silencing (hypermethylation), ER-and PgR-negative status, an earlier age of onset and high tumor grade resemble phenotypically BRCA1 mutated cancers termed 'BRCAness', those with no BRCA mutations but with a dysfunction of the DNA repair system. In conclusion, genetic or epigenetic loss-of-function mutations of genes that are known to be involved in the repair of DNA damage may lead to increased risk of developing a broad spectrum of breast and ovarian cancers.

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Section: Lynch Syndromementioning

confidence: 88%

Hereditary breast and ovarian cancer susceptibility genes (Review)

et al. 2013

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“…The second most common cancer in Lynch syndrome is endometrial adenocarcinoma with a lifetime risk of around 60%. [7][8][9][10] In fact, endometrial cancer frequently presents as an index cancer in women with Lynch syndrome. 11,12 However, the majority of cancers with MSI are caused by somatic methylation of the MLH1 promoter region that silences gene expression in the tumor tissue, rather than germline mutations of MMR genes.…”

Section: Discussionmentioning

confidence: 99%

Cancerous ‘floater’: a lesson learned about tissue identity testing, endometrial cancer and microsatellite instability

et al. 2013

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A 46-year-old woman presented with endometrial cells on a pap smear and underwent endometrial curettage. The specimen revealed secretory endometrium and a possible endometrial polyp. In addition, a single 4 mm fragment of well-differentiated adenocarcinoma was found. Tissue identity DNA genotyping was performed and the adenocarcinoma tissue fragment showed a drastically different allelic pattern from that of the background endometrium. To confirm tissue contamination, genotyping of three other tumor specimens-probable sources for a contaminant-was performed but failed to identify a match. Without confirmation of contamination, a second endometrial curettage was obtained from the patient, in which similar adenocarcinoma tissue was once again found. Further workup demonstrated that the patient had a microsatellite unstable (MSI) endometrial adenocarcinoma by immunohistochemistry and molecular testing. The patient subsequently underwent staging surgery, which revealed an early-stage, well-differentiated endometrioid adenocarcinoma. This case study illustrates an uncommon, yet important caveat of tissue identity testing by DNA genotyping, where MSI instability can significantly alter the allelic pattern of DNA polymorphisms in the tumor genome, leading to erroneous conclusion regarding the tissue identity. Awareness of this phenomenon is crucial for a molecular pathologist to avoid interpretation errors of tissue identity testing in a cancer diagnostic workup.

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“…In patients with Lynch syndrome, Schmeler et al (20) found that the median age at diagnosis of endometrial and ovarian cancer was 46 and 42 years, respectively, with diagnosis at ≥35 years in 94 and 83% of the cases, respectively. These findings suggested that the more appropriate indication for RRS is 'a woman aged 35 years or older not desiring to bear children, or a postmenopausal woman with suspected Lynch syndrome from family history or known DNA mismatch repair gene mutation' (21). Moreover, since endometrial cancer in Lynch syndrome is mainly detected at an early stage (12), treatment initiated following early detection may be curative (22).…”

Section: Indications For Rrsmentioning

confidence: 99%

Risk-reducing surgery in hereditary gynecological cancer: Clinical applications in Lynch syndrome and hereditary breast and ovarian cancer

Adachi

Banno

Yanokura

et al. 2014

Molecular and Clinical Oncology

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Abstract. Risk-reducing surgery (RRS) is defined as a prophylactic approach with removal of organs at high risk of developing cancer, which is performed in cases without lesions or absence of clinically significant lesions. Hereditary gynecological cancers for which RRS is performed include hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. For HBOC, RRS in the United States (US) is recommended for women with mutations in the breast cancer susceptibility (BRCA)1 and BRCA2 genes and bilateral salpingo-oophorectomy (BSO) is generally performed. This procedure may reduce the risk of breast, ovarian, Fallopian tube and primary peritoneal cancer, although ovarian deficiency symptoms occur postoperatively. For Lynch syndrome, RRS in the US is considered for postmenopausal women or for women who do not desire to bear children and BSO and hysterectomy are usually performed. This approach may reduce the risk of endometrial and ovarian cancer, although ovarian deficiency symptoms also occur. For RRS, there are several issues that must be addressed to reduce the risk of cancer development in patients with HBOC or Lynch syndrome. To the best of our knowledge, this is the first review to discuss RRS with a focus on hereditary gynecological cancer. IntroductionHereditary gynecological cancers include ovarian cancer associated with hereditary breast and ovarian cancer (HBOC); endometrial and ovarian cancer associated with Lynch syndrome; endometrial, cervical and ovarian cancer associated with Peutz-Jeghers syndrome; and ovarian cancer associated with Cowden disease. HBOC is an autosomal dominant hereditary disease that may cause breast, ovarian, Fallopian tube and peritoneal cancer.Mutations of the breast cancer susceptibility (BRCA)1 and BRCA2 genes have been identified in ~8-13% of patients with ovarian cancer (1,2). By the age of 70 years, the estimated risks of developing ovarian cancer are 35-60 and 10-27% in BRCA1 and BRCA2 mutation carriers, respectively (2). The mean ages at diagnosis of ovarian cancer are 54, 62 and 63 years for BRCA1 and BRCA2 mutation carriers and non-carriers, respectively, indicating that BRCA1 mutation carriers are more likely to be affected by ovarian cancer at a younger age (3). Clinicopathologically, the majority of ovarian cancers that are BRCA1/2 mutation-positive are of serous histology and are poorly differentiated (grade 3) stage III-IV tumors, according to the International Federation of Gynecology and Obstetrics (FIGO) staging criteria, as defined in 1988 (4,5). In BRCA1/2 mutation-positive and -negative cases, the rates of serous adenocarcinoma are 63-86 and 57-58%, those of poorly differentiated tumors 68-87 and 48-58% and those of stage III-IV tumors 72-88 and 62-70%, respectively.Lynch syndrome, also referred to as hereditary non-polyposis colorectal cancer, is an autosomal dominant hereditary disease that may lead to colorectal, endometrial, gastric and ovarian cancer. Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes, which include mu...

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Endometrial Cancer and Lynch Syndrome: Clinical and Pathologic Considerations

Cited by 219 publications

References 41 publications

Hereditary breast and ovarian cancer susceptibility genes (Review)

Hereditary breast and ovarian cancer susceptibility genes (Review)

Cancerous ‘floater’: a lesson learned about tissue identity testing, endometrial cancer and microsatellite instability

Risk-reducing surgery in hereditary gynecological cancer: Clinical applications in Lynch syndrome and hereditary breast and ovarian cancer

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