Navigating the Unknown: How International Lynch Syndrome Awareness Day, 22 March, Serves as a Guiding Constellation for Romania

The executive committee of the Romania Society of Lynch Syndrome: MD PhD Oana Cristina Voinea - President, MD PhD Lucian Eftimie - Vicepresident; MD PhD Adrian Dumitru- Vicepresident; Maria Sajin – Honorific president;  MD Teodor Constantin, secretary. srsl.ro; contact@srsl.ro

Abstract: Lynch syndrome, formerly known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), characterized by a defective DNA mismatch repair, is the most common autosomal dominant hereditary predisposition to several malignancies. LS patients typically exhibit an elevated risk of developing multiple primary malignancies with early onset. The most commonly involved organs are those with an accelerated cellular turnover. The colon and endometrium are the most commonly affected sites, however, the spectrum of neoplastic involvement extends beyond these organs and can involve the entire digestive tract, ovarium, urothelium, skin, and breast with varying incidences depending on the specific pathogenic variants affecting the MMR genes (MLH1, MSH2, MSH6, PMS2 and EPCAM).

A conservative estimate suggests that the prevalence of mutations associated with Lynch syndrome in the general populations is 1 in 279 individuals. Over the last 25 years, significant advancements have been achieved comprehending the biology of cancers related to Lynch syndrome, alongside developing strategies for cancer prevention, risk mitigation, and targeted therapies. In Western countries, advancement in medical research and practice have led to the establishment of national programs that offer comprehensive approaches to diagnosis, screening, and targeted treatment options for Lynch syndrome patients.

Romania lacks an oncogenetic program, which means that this disease, despite its personal and familial impact, remains opportunistically diagnosed. It is the most prevalent hereditary autosomal disease with oncological manifestations and yet no screening programs or targeted treatment protocols are available for Romanian patients with Lynch Syndrome.

The Romanian healthcare system needs to align with the oncogenetics models of the Western world, which provide tailored screening and treatment programs for patients and their families. This article underlines the international position regarding prophylactic measures, diagnostic and treatment programs for Lynch syndrome and aims to motivate Romanian healthcare professionals to take action.

What is Lynch Syndrome?

Lynch syndrome is the most common hereditary predisposition to cancer syndromes, which recognize an autosomal dominant model of transmission. It was found in 1 of 35 patients with colorectal carcinoma [1, 2] and 1 of 56 patients with endometrial carcinoma [3] respectively. While its main symptoms are represented by colorectal and endometrial cancers, many other sites can contribute to the complex spectrum of manifestations. Since the genetic mechanism that steers the manifestation of cancers consists in a lack of structural or functional capacity of the proteins to repair the mistakenly copied DNA (mismatch repair proteins), tissues with an accelerated turnover are prone to a precipitated process of carcinogenesis. Four main genes have been identified as being involved in and defining Lynch syndrome: MLH1, MSH2, PMS2, and MSH6. The malfunctioning variants are referred to as path_MLH1, path_MLH2, path_MSH6, and path_PMS2. People carrying inherited path_MMR or inherited epigenetically silenced variants of these genes are referred to as “carriers” [4]. Depending on which gene is involved, a different predisposition for various cancer types can be identified for each patient: the risks for colorectal cancer, ovarian cancer, gastric and small bowel cancer, urothelial cancer, skin tumors, benign or malignant, and cancer of the central nervous system [5] are summarized below.

Table 1. Cumulative risk for carcinomas associated with Lynch Syndrome for each of the 4 genetic mutations, according to the NCCN Guidelines, Version 1.2022 Lynch Syndrome

Lynch syndrome was first described by Henry T. Lynch et al. in 1966 [5]. He analyzed the genealogy of “family G”, a topic of primary interest to his professor, A. S. Warthin. In 1895, Family G became the subject of a paper which was the first to mention the hypothesis of a “cancer family syndrome”. Upon studying more than 650 descendants from “family G”, of which 95 had developed malignant lesions, Lynch concluded that cancer involving specific anatomic sites is consistent with an autosomal dominant inheritance pattern [6]. The study of family G continued in the context of the evolution of medicine. In 2005, Douglas et al. studied 929 descendants and identified a specific mutation in the MSH2 gene, responsible for the predisposition to colorectal and endometrial cancers [7]. Meanwhile, using PCR techniques, the genetic deletions found in the cancer DNA of the patients with a familial predisposition to certain cancers received the name of “microsatellite instability” [8,9]. Several other families with cancers that were microsatellite unstable were studied and additional mutated genes were identified. Along with MSH2, MLH1, PMS2, and MSH6 were also identified [10, 11, 12, 13].

The dynamic evolution in understanding Lynch Syndrome’s biology has triggered an active interest in identifying individuals who carry specific mutations, as well as in developing methods of prediction. This active interest led to the development of several diagnostic algorithms aimed at facilitating the early diagnosis of Lynch syndrome.

Several clinical diagnostic criteria were proposed, but the Amsterdam and Bethesda guidelines are the ones that remain in current practice, after revision and updating. The Bethesda criteria, first elaborated in 1997 and later revised in 2004 [14], were designed to guide the assessment of microsatellite instability, which includes the evaluation of two or more family members diagnosed with Lynch-related cancers. The original Amsterdam criteria for Lynch syndrome, which applied to families with three or more cases of colorectal cancer, were first published in 1994. They were revised in 1999 to include extracolonic tumors, such as endometrial, urinary tract, and small bowel cancer [15, 16].

Amsterdam II Revised Criteria - All of the following criteria should be met:

• • Three or more blood relatives with a Lynch-related cancer (CRC, endometrial, small bowel, ureter, or renal pelvis)
• • One relative must be a first-degree relative of the other two
• • One or more cancer cases diagnosed before the age of 50 years
• • Two or more successive generations affected
• • Familial adenomatous polyposis excluded in CRC
• • Tumor diagnosis confirmed by histopathologic examination

Revised Bethesda Guidelines - At least one of the following criteria should be met:

• • CRC or endometrial cancer diagnosed before the age of 50 years
• • Synchronous or metachronous CRC or other LS-associated tumors, regardless of age
• • Colorectal cancer with MSI-high-associated morphologic features (Crohn-like lymphocytic reaction, mucinous/signet cell differentiation, or medullary growth pattern) in a patient younger than 60 years
• • CRC in a patient with one or more first-degree relatives with an LS-associated tumor, with one of the cancers being diagnosed before the age of 50 years
• • CRC diagnosed in two or more first- or second-degree relatives with LS-associated tumors, regardless of age

Because none of them provides 100% specificity or sensitivity, a workshop dedicated to Lynch syndrome was held in Jerusalem in 2010, which recommended that any person with colorectal cancer younger than 70 years old should be screened for microsatellite instability (using PCR or IHC testing) to detect possible Lynch syndrome [17].

The current recommendations for detecting Lynch syndrome, according to the European guidelines from EHTG and ESCP for Lynch Syndrome, the 3rd edition (2021), NCCN Guidelines for Genetics/Familial High Risk Assessment 1/2021, and ASCO CAP guidelines (2022), conclude that the clinical criteria alone are not sufficient to guide tumor testing due to their low sensitivity in detecting patients with LS [4, 18, 19]. The recommendations are consistent with a general screening for microsatellite instability using PCR or IHC for MMR in all cases of colorectal and endometrial cancer. Further tests are directed to somatic or germline mutation detected by NGS in order to conduct a targeted screening program for individuals carrying this diagnosis, as well as for determining eligibility for using immunotherapy, which is already available in Western countries.

Lynch syndrome often goes undiagnosed in Romania due to a lack of standardized procedures for clinical, immunohistochemical, or molecular biological diagnosis. Individuals carrying this mutation are usually diagnosed via immunohistochemistry, but no further standardized surveillance is provided for them. In rare cases, oncologists, gynaecologists, or gastroenterologist may refer patients to genetic counseling, but an integrated surveillance system is missing. Also, despite the promising results and the wide use of immunotherapy for tumors that show microsatellite instability in Western countries, the Romanian treatment guidelines do not include this option.

Lynch syndrome is the most common hereditary autosomal dominant transmitted condition that predisposes carriers to a high risk of malignancy and it requires integrated, standardized diagnostic, screening and treatment procedures in line with Western principles. WHO criteria for screening implementation are stated since 1970 [20].  We expose the problems related to Lynch Syndrome in Romania in light of the above-mentioned criteria:

1. (1) The condition sought should be an important health problem.

According to GLOBOCAN, in Romania colorectal cancer occupies the first place regarding incidence of malignancies in both sexes, and in terms of mortality, colorectal cancer is the second killer, after pulmonary cancer. By 2030, the incidence of early-age onset CRC diagnosed under the age of 50 years is predicted to increase by more than 140% [21].

Endometrial carcinoma, the most frequent form of genital cancer in developed countries, ranks 6th in female cancer incidence in Romania. By 2040, it is estimated to increase by more than 50% worldwide [22]. Lynch syndrome is responsible for almost 9% of endometrial cancers in premenopausal females [23].

Large studies concluded that 3-5% of all colorectal cancers and 2-6% of endometrial carcinomas are driven by mutations that define Lynch syndrome [24-26].

1. (2) There should be an accepted treatment for patients with a recognized disease.

Treatment of LS patients varies depending on the moment when the mutation is diagnosed.

For primary prevention, there are several options for reducing of developing cancer. First and foremost, basic lifestyle changes can be made to promote healthy habits, such as quitting smoking, exercising and dietary improvements, as well as chemoprevention – aspirin, progestine, oral contraceptives, or vaccines. Additionally, surgical procedures can be undertaken, in high-risk families, with early onset of different cancers, especially for MLH1, MSH2, and MSH6. For patients with advanced disease, immune checkpoint inhibitors represent the first line treatment for metastatic microsatellite unstable colorectal carcinomas recommended in US guidelines since 2018, as well as in European Guidelines. These therapies are currently unavailable for Romanian patients.

The potential therapeutic effect of Aspirin at a daily dose of 600 mg for the prevention of colorectal cancer in Lynch syndrome patients was initially reported in 1988 [27]. Subsequent studies have validated this hypothesis. The most recent studies, spanning a surveillance period of 10 years, demonstrate a significant difference for this endpoint (colorectal cancer) when aspirin was compared to placebo [28]. The actual struggle is in finding the optimal dose that can reduce the colorectal carcinogenesis with minimal side effects [29].

In the context of endometrial carcinoma and ovarian carcinoma, exogenous progestins have been acknowledged for their efficacy in diminishing the lifetime risk of developing these malignancies, regardless of MMR status [30-32]. The use of depo-medroxyprogesterone acetate or combined oral contraceptives was studied. The findings revealed a remarkable reduction in endometrial proliferation and provided evidence for their chemopreventive efficacy [33].

The remarkable immune response of malignant lesions associated with Lynch syndrome led to the hypothesis that a vaccine could be able to reduce the risk of cancer [34]. At present, there are no approved vaccines for cancer prevention, but clinical trials are ongoing.

Risk reducing surgery: A subtotal colectomy in selected patients, depending on the colonoscopy result, proved to reduce the risk of a colorectal carcinoma [35], but there is no guideline to recommend this procedure for primary prophylaxis. Prophylactic hysterectomy, along with bilateral salpingo?oophorectomy (HBSO), is recommended women with Lynch syndrome after menopause or after completing their childbearing [36]. According to the third edition of the Mallorca guidelines, prophylactic colorectal surgery in the absence of neoplastic lesions in the colorectum is not recommended for path_MMR carriers based on their pathogenic variant-related risk only [4].

In recent years, a novel therapeutic options has emerged for the treatment of advanced tumors in Lynch Syndrome patients. Used as a first line treatment for colorectal and endometrial carcinoma for metastatic patients, immunotherapy using checkpoint inhibitors are stipulated in the NCCN guideline [19], ASCOCAP recommendations [37] and ESMO clinical practice guidelines [38]. Due to its absence from national treatment guidelines, immunotherapy is currently not available to Romanian patients. Individuals in Romania who wish to access the same medicines available to patients in Western countries must pay the full cost of treatment, which can be a deterrent for a lot of people. People need equal opportunities for treatment and equal chances to live!

1. (3) Facilities for diagnosis and treatment should be available.

Adequate clinical criteria for Lynch syndrome are considered obsolete for patients who are already symptomatic with colorectal, endometrial, or ovarian carcinoma, according to current international guidelines, as they lack both sensitivity and specificity. An international consensus has been reached regarding universal immunohistochemical screening of colon and endometrial cancer specimens. [19, 37, 38]. A number of studies have demonstrated that biopsy or surgical resected specimens exhibit similar levels of accuracy with respect to the results obtained from the four canonical antibodies, namely MLH1, MSH2, PMS2, and MSH6 [19]. In Romania, immunohistochemical diagnose is feasible but it is not supported by any national protocol. This screening test is readily available in various hospitals and private laboratories, and the expenses are typically covered by the national health insurance system. However, testing is done sporadically and inconsistently. Due to the possibility of false positive or false negative results, MSI status and BRAF mutation testing are recommended to ensure accurate results. For the somatic mutation that increases the risk of carrying this mutation across generations, genetic testing using NGS is recommended. At present, the national health insurance system in Romania does not provide coverage for either NGS genetic testing or PCR testing for MSI status or BRAF mutation.

The proposed diagnostic algorithm by ESMO and WHO [39, 40] is synthesized in the figure (Figure 1) below:

Figure 1. The diagnostic algorithm for specimens of colorectal or endometrial carcinoma. Immunohistochemistry (IHC) is used for MMR deficiency, testing the positive or negative staining of the 4 antibodies, MLH1, MSH2, PMS2, and MSH6. The PCR technique can be used for MSI testing and can identify the hypermethylation state of MLH11 that is missed by IHC, leading to a false negative result.

The recommendation for families of the index patient is to undergo genetic testing. In cases where patients decline genetic testing, alternative screening options should be considered. The identification of carriers through genetic testing of the index patient’s family members has been demonstrated to be a cost-effective strategy [41, 42].

1. (1) There should be a recognizable latent or early symptomatic stage.

One of the hallmark features of colorectal cancer associated with Lynch syndrome is an accelerated carcinogenesis that drives a rapid progression from diminutive adenoma to adenocarcinoma within a period of merely 2-3 years, which stands in contrast to the typical 6 to 10 year interval required for sporadic adenoma to become malignant [43]. Each gene gives a different contribution to the LS spectrum, depending on the specific role in the MMR machinery. The cumulative lifetime risk of cancer in LS carriers varies in the different organs and is influenced by various factors, including gender, age, specific gene mutation, and population [44].

Early stage cancers in symptomatic Lynch Syndrome patients may be indicative of the disease at an earlier stage, highlighting the importance of early detection and management. In the case of colorectal cancer, adenomas are initiate a carcinogenic cascade. Similarly, atypical endometrial hyperplasia is a precursor lesion that predisposes to endometrical cancer. However, these can be readily detected by implementing a comprehensive and meticulous screening program. Occasionally, colorectal adenomas may present with symptoms such as altered bowel habits, hematochezia or anemia, but they are generally asymptomatic. Colonoscopy remains the golden standard for adenoma diagnoses.  Endometrial hyperplasia with atypia, on the other hand, is more likely to be symptomatic, with abnormal uterine bleeding being the cardinal symptom. Other organs that are susceptible to malignancy may exhibit subtler symptoms, and dysplasia of the epithelium in such cases may be difficult to assess. In Lynch syndrome patients, regular endometrial biopsies are recommended to mitigate such challenges [4, 37].

1. (2) There should be a suitable test or examination;
2. (3) The test should be acceptable to the population.

The diagnosis of Lynch syndrome, as a genetic disease with an autosomal dominant model of transmission, can be established in the index patient through a diagnostic algorithm that includes IHC for MMRd proteins, PCR for microsatellite instability, or NGS for somatic mutations

Lynch syndromes diagnose, as a genetic disease with autosomal dominant model of transmission, can be diagnosed on the index patient, according to the algorithm shown above, using IHC for MMRd proteins, PCR for microsatellite instability of NGS for somatic mutations (germline mutations can also be detected using tumor tissues for the purpose of treatment studies) [45].

Immunohistochemistry uses antibodies to bind and stain the proteins of mismatch repair, MLH1, MSH2, PMS2 and MSH6. The absence of at least one of these proteins can help clinicians identify the gene that is likely to contain the pathogenic variant.  Additionally, microsatellite instability is detectable by polymerase-chain-reaction (PCR) analysis. It can be used as an alternative, but, unlike immunohistochemistry, it does not indicate which gene could be affected. It has also been shown that the accuracy of microsatellite instability is reliable in colorectal cancer; it may be less accurate in endometrial cancer [46].

All the aforementioned tests are deemed clinically suitable for both patients and physicians alike. The required tissue samples for performing IHC or MSI are obtained from the tumor tissue itself, while genetic testing relies on a patient’s blood samples. In Romania, only IHC testing is currently available with no additional costs to the patient. MSI and NGS for Lynch Syndrome are currently not covered by the national health insurance system in Romania.

Due to the increased predisposition to multiple cancers in patients with Lynch syndrome (Table 1), and their usual early onset, screening measures are essential for early detection. International recommendations are summarized in the table below. It provides a brief overview of, guidelines incorporating  recommendations from a range of sources, including the NCCN guidelines [19], ASCOCAP [37], the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG) [47], The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome [48], The updated third edition of the Mallorca guidelines based on gene and gender[4], Associon Francaise de Formation Medicale Continue en Hepato-Gastro-Enterologie (FMCGastro) [49] and European Society of Gynecological Oncology/ESGO former Advisory Committee for Radiation Oncology Practice (ACROP)/European Society of Pathology (ESP) ESGO/ESTRO/ESP guidelines [50].

Table 2. International recommendations regarding surveillance strategies for colorectal and endometrial carcinoma in Lynch Syndrome patients.

It is likely that Romanian people could benefit from the measures recommended by international guidelines, as they are based on evidence-based research and taking into consideration that they are already being applied in Western societies.

1. (1) The natural history of the condition, including development from latent to declared disease, should be adequately understood.
2. (2) There should be an agreed policy on whom to treat as patients.

Lynch Syndrome is the leading autosomal dominant genetic cause of predisposition to malignancy in adults. Even though it is estimated that 1 in 273 persons carries one of the mutations that define this syndrome, it remains underdiagnosed worldwide. Educational programs are needed, for both patients and medical personnel. In the realm of clinical practice, an increased awareness must start from the confines of the general practitioner’s office. The family doctor, who knows the genealogy and the familial medical history of his patients, should be attentive to suggestive signs of an oncological disease, in accordance with the Amsterdam and Bethesda criteria, which may necessitate a referral for a genetic consult. Pathologists, gastroenterologists, oncologists, and gyneacologist should also ask for additional diagnostic tests in cases where IHC reveals a MMRd status.All stakeholders should be informed of the impact of Lynch syndrome on the predisposition for certain malignancies.

Following diagnosis, patients with Lynch syndrome in Romania currently do not have access to targeted healthcare options specific to their condition through the existing national healthcare system. A personalized screening program is not available and targeted therapeutic options are not provided through the national medical system. The psychosocial implications associated with a hereditary cancer predisposition syndrome are difficult to quantify, and are equally challenging to manage, given the infrequency of requests for genetic counseling.

The paradigm regarding genetic syndromes must change! People that carry Lynch Syndrome mutations lack any physical or intellectual particularities. To put the frequency into perspective, it is highly likely that every one of us has a neighbor who carries this disease, whether they are aware of it or not. Moreover, any one of us could be said neighbor. Currently, only time can tell. However, a systematic program dedicated to the optimization of diagnostic and management for this specific population can improve outcomes and quality of life for our Lynch Syndrome suffering neighbor.

1. (3) The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole.

The benefit of early recognition of malignancy is translated in a higher life expectancy, an improved quality of life, an economic advantage related to the cost of high stage cancers vs. curable ones. Several studies have found that the recommended Lynch syndrome tumor testing is clinically and cost-effective [51]. A systematic review of 20 studies concluded that Universal or <70 years–age-targeted CRC-based LS screening programs are cost-effective [52]. The reality of oncogenetic networks in the western countries [Figure 2], is the living proof that a systematic dedicated program it is urgently needed for Lynch Syndrome patients from Romania.

Figure 2. The geographic repartition of the centres were the main oncogenetic disease are diagnosed and therapeutically managed. [53 ]From Oncogénétique en 2020 /consultations & laboratoires, suivi en 2019 et 2020, collection Appui à la décision, Institut national du cancer, juin 2022.

1. (4) Case-finding should be a continuing process and not a "once and for all"project.

A new approach, tailored to each individual patient’s unique characteristics and leveraging the altest advances in diagnostic and therapeutic technologies is imperative in the management of Lynch syndrome.

The Romania Society of Lynch Syndrome is striving to become the frontrunner in establishing a comprehensive national oncogenetic network that will cater to the needs of Lynch syndrome patients across the country. Our aims include:

• • Personalised screening programs and preventive measures
• • Novel opportunities in treatment and prevention
• • The implications of the hereditary pattern of transmission

To effectively implement such a network, it is imperative to establish supportive legislative frameworks, secure sustainable financing, and demonstrate a determined commitment to align our preventive healthcare systems with Western standards.

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