Screening and surgical prophylaxis for hereditary cancer syndromes with high risk of endometrial and ovarian cancer

Abstract

In the era of advanced cancer genomics, our recognition of hereditary cancer mutations continues to increase. Two of these conditions, which carry an increased risk of female cancers including endometrial, ovarian, breast, are hereditary breast and ovarian cancer syndrome and Lynch syndrome. Risk-reducing surgery, such as mastectomy, salpingo-oophorectomy, and hysterectomy may decrease cancer risk for mutation carriers. Background, indications, techniques, and consequences of these surgical procedures are reviewed.BRCA, endometrial cancer, hereditary cancer, Lynch syndrome, ovarian cancer | INTRODUCTIONIn 2019, over 109 000 women in the United States will be diagnosed with gynecologic malignancy and over 33 000 will die from one. 1 Although only a small percentage of these women will develop endometrial or ovarian cancer associated with an identifiable germline mutation, the potential for personalized prevention and individualized treatment is great in this select cohort. This article will review the hereditary conditions associated with increased risk of ovarian and/or endometrial cancer and how patients should be screened for these mutations. It will also address the surgical means by which these women can reduce their risk of ovarian and endometrial cancer. | HEREDITARY BREAST AND OVARIAN CANCER SYNDROMEIn 2018, approximately 22 000 women received a new diagnosis of ovarian cancer in the United States, and there were 14 000 ovarian cancer deaths. 2 Inherited germline mutations that increase the risk for ovarian cancer are present in approximately 7%-25% of these women. 3 Hereditary breast and ovarian cancer syndrome (HBOC) is the most common genetic syndrome linked to ovarian cancer and is associated with mutations in the BRCA genes. BRCA1 and BRCA2 are tumor suppressor genes involved in the repair of double-stranded DNA breaks. Certain populations are at significantly higher risk for BRCA mutations than the general population including, Ashkenazi Jewish, French Canadian, and Icelandic populations. This is because of the founder effect, which causes a decrease in genetic diversity in a population that is geographically or reproductively isolated. For example, in the general United States non-Jewish population, the risk of inheriting a BRCA mutation is 1 in 400 compared with the Ashkenazi Jewish population, who carry an increased risk of 1 in 40. 4 The inheritance pattern of the BRCA mutations is autosomal dominant. However, tumor suppressor genes are known to be recessive, requiring both copies of the gene to be affected. In the "two-hit" hypothesis, a loss of heterozygosity is required. Therefore, a germline BRCA mutation is inherited in one copy of the gene, the second copy then undergoes a somatic mutationi.e., the second hitand the carrier is phenotypically affected. 5The most recently estimated cumulative cancer risk by age 80 for BRCA1 and BRCA2 carriers is 72% and 69%, respectively. 2 By comparison, the lifetime risk of ovarian and breast cancer in the general population is 1.3% and 12.4%, respective...

Das Lynch-Syndrom als bedeutendes erbliches Tumorsyndrom

“…In seltenen Fällen können auch Deletionen in dem EPCAM-Gen, das nicht zu den MMR-Genen gehört, zu einem epigenetischen "Silencing" von MSH2 führen [2 -4]. Wie bei den BRCA-Genen beim erblichen Brust-und Eierstockkrebs wird die Mutation in den MMR-Genen dominant vererbt, erfordert aber einen "Second Hit", um das zweite MMR-Allel zu inaktivieren und so zu einer defekten DNA-Mismatch-Reparatur zu führen [3]. Diese resultiert dann in einer Prädisposition für zahlreiche Karzinome (▶ Tab.…”

“…Man schätzt, dass bei etwa 1 % der Frauen, die an einem Ovarialkarzinom (OC) erkranken, ein LS vorliegt [3]. In einer deutschen unselektierten Fallserie von 523 Frauen mit primären oder rezidivierten Ovarialkarzinomen, bei denen nach genetischer Beratung eine Untersuchung auf Mutationen u. a. in MLH1, MSH2, MSH6 und PMS2 durchgeführt wurde, fand man in 0,6 % pathogene Varianten: 2-mal MSH2 (1 High-grade seröses OC, 1 High-grade ▶ Tab.…”

“…Bei alleiniger Anwendung der ärztlichen Anamnese (Amsterdam/Bethesda-Kriterien, s. Kasten) bei Frauen mit EC werden 25-50 % der LS nicht detektiert [1,3,25]. Zu berücksichtigen ist auch, dass eine entsprechende qualifizierte Anamnese nicht immer durchgeführt wird [25].…”

“…Daneben können in beiden Geschlechtern noch zahlreiche andere Malignome auftreten. Die früher übliche Bezeichnung "(HNPCC)" wird diesem Sachverhalt nicht gerecht und ist nach einem der Erstbeschreiber durch den Terminus "Lynch-Syndrom" ersetzt worden [3]. Das LS wird verursacht durch pathogene Keimbahnvarianten von DNA-Mismatch-Reparatur-Genen, die zu Fehlern bei der DNA-Replikation führen [2].…”

Lynch Syndrome and Breast Cancer: Case Reports and Literature Review

“…Patients with LS are carriers of mutations in one of four DNA MMR genes: MLH1, MSH2, MSH6, PMS2 or the EPCAM gene upstream of MSH2 leading to its inactivation. More specifically MLH1, MSH2, MSH6 and PMS2 mutations in this syndrome account for approximately 37%, 41%, 13% and 9% respectively [2]. The total risk of breast cancer up to 70 years of age in MLH1 carriers is 18.6% and in MSH2 carriers 11.2% [3].…”