Endometrial cancer is the most commonly diagnosed gynecologic cancer in women worldwide [27], and approximately 2–12% of patients carry germline mutations in cancer predisposition genes [28–30]. It is usually diagnosed at an early stage, as the first symptom - vaginal bleeding - occurs, and therefore has a good prognosis [31, 32]. The median age at diagnosis is 68 years [33]. Ovarian cancer is less common but is usually diagnosed at late stages. About 10–20% of OC are due to hereditary predisposition [1]. About 5% of endometrial cancers and 10–20% of ovarian cancers are synchronous (the two primary cancers are diagnosed within 6 months) [31, 32]. Synchronous endometrial and ovarian carcinoma (SEOC) accounts for 50–70% of all synchronous gynecologic cancers in women [34]. The typical histology of SEOC is endometroid adenocarcinoma of both the endometrium and ovary, which has been described in up to 70% of cases [1]. The presented clinical case was a postmenopausal 52-year-old woman with histologically verified endometroid adenocarcinoma of the endometrium and synchronous endometroid ovarian cancer. Thus, our case confirms that the majority of SEOC cases have endometroid adenocarcinoma in both the endometrium and ovary.
The presence of SEOC is an independent indication for the evaluation of Lynch syndrome [20]. In our case, there were two other indications for suspicion of hereditary cancer - the endometroid histology of both tumors and the family history of the proband. All these features were the reason for the referral of the presented patient to our genetics department. Because the clinical data indicated LS, we expected to find a pathogenic germline variant in the MMR gene. Instead, the result of the germline gene test was a likely pathogenic variant (c.4109del) in the WRN gene.
The WRN gene encodes the WRN helicase, which belongs to the RecQ family of helicases [35]. In humans, there are five different RecQ helicases - RecQ1, BLM, WRN, RecQ4 and RecQ5. They belong to the family of DNA unwinding enzymes that are essential for maintaining genomic stability by repairing damaged DNA, signaling DNA damage, maintaining telomeres, base excision repair, and homologous recombination. The five helicases have similar domains: the core helicase domain, the RecQ C terminal domain and the helicase and RnaseD-like C-terminal (HRDC) domain [36]. Biallelic inactivation of the WRN gene results in autosomal recessive Werner syndrome (OMIM 277700), which is characterized by a premature aging phenotype, short stature, early graying, bilateral cataracts, and other features [37]. In vitro experiments confirmed that cell lines in the case of a heterozygous state (monoallelic carrier state of the pathogenic variant) have reduced WRN proteins and helicase activity, which could predispose to cancer [38].
The pathogenic/likely pathogenic variants in the WRN gene reported to date account for 324, one-third of which are frameshift and, less frequently, nonsense and splice-cite mutations [39]. In the present case, we have discovered a likely pathogenic variant - a frameshift mutation that is the result of a deletion of adenine at 4109 site of the WRN nucleotide sequence (1370 aa site in the protein). This variant results in alteration of the WRN protein after 1370 aa and shortening after 23 amino acids. The truncation of the WRN gene leads to a loss of nuclear localization signal (NLS) in the C-terminal region (aa1370-1375) and, in addition, the altered WRN protein could not be transported into the nucleus [40].
The detected variant is not present in the population database (GnomAD) but has been identified in affected individuals in a Chinese family [41]. One of the affected relatives in the Chinese family developed endometrial cancer at the age of 55 years, which is consistent with the clinical data of our case (diagnosed at the age of 52 years). In addition, the truncated variant was confirmed in two other affected females from the Chinese family. Strikingly, our proband and the affected individuals from the Chinese family are all women. Probably, this fact is not a coincidence and this variant in the WRN gene shows expression predominantly in the female sex, but this fact needs further investigation. In our case, the other affected family members are also female, but they are no longer alive and we could not confirm the carrier status of the WRN variant, but based on their clinical data, we suspect that they were also carriers of the familial WRN variant. One of the affected family members, from our case, was diagnosed with breast cancer, and it is known that pathogenic WRN variants were found quite frequently (2.95%) in breast cancer patients [42]. The other family member was diagnosed with ovarian cancer, which is not as common in WRN mutation carriers but is part of the Lynch syndrome cancer spectrum. Our proband's sister (healthy, 48 years old) underwent genetic testing at another laboratory and informed the genetic counselor that she was negative for a familial variant in the WRN gene.
In the present clinical case, the detected pathogenic variant is in the heterozygous state and has not been confirmed in unaffected relatives. Since WRN mutations (WRN-mut) in cancer lead to genomic instability and in order to establish the correct correlation between the pathogenic germline variant and the clinical diagnosis, the genetic counselor recommended a histological IHC evaluation of the MMR status of the proband's tumor tissue. The result showed that the tumor was MMR deficient (no expression of MLH1 and PMS).
All clinical, familial, genetic and histological data of our clinical case lead to the final conclusion that this case is a hereditary LLS.
The cumulative risk of developing cancer at age 70 was found to be higher in LLS than in the general population and lower than in LS. Nevertheless, these patients and their families should be considered at high-risk and eligible for prevention strategies [19]. There are different recommendations for prevention in LLS patients and their first-degree relatives, those that make the recommendation similar to LS with longer surveillance intervals [18] and others that take into account the age for diagnosis of LLS (between the age for the general population and the age at LS) and family history [43]. Considering the family history of the presented clinical case, we gave the proband the compiled recommendation for prevention - a clinical examination of the breasts every 6 months to 1 year and a mammography/MRI of the breasts once a year and because in LLS the most commonly affected organ is the colon - in our case a high quality colonoscopy to be performed and repeated every 3 years.
The presented clinical case could contribute to the identification of the etiology of LLS. Based on the combined information from clinicians, pathologists, genetic counselors, and big data from NGS testing for cancer predispositions, clinical surveillance and follow-up management in women with gynecologic cancers, especially SEOC, could be improved.