Introduction

The most common inherited cancer syndrome that increases individual risk for colon cancer is Lynch syndrome. It is caused by Mismatch Repair deficiency due to a germline pathogenetic variant of MMR gene (MLH1, MSH2, MSH6, PMS2, EPCAM) . The introduction of multigene testing has improved and speeded up the diagnosis but has also increased the chance of finding a variant of uncertain significance (VUS) for a clinical point of view. The clinical features and management of these cases is still not clearly defined.
The aim of the present study was to determine the frequency of VUS in patients with clinical suspicion of Lynch syndrome and to define their clinical characteristic compared with Lynch affected.

Aims & Methods

Patients referred to the Centre of reference for hereditary colorectal cancer syndromes of our institution, who performed multigene testing from 2017 to 2022 for suspicion of Lynch syndrome, were retrospectively evaluated. Demographics, clinical data and oncological family history were recorded.
Genetic analysis of probands was performed using Next Generation Sequencing technology. Variant classification was performed according to the InSiGHT database (https://www.insight-group.org/variants/databases) or the the InSiGHT Variant Interpretation Committee (VIC) MMR gene variant classification criteria.
Patients were divided into three groups according to the results of genetic testing: pathogenetic variant (Lynch syndrome affected, LS), Variant of uncertain significance (VUS) or a negative result.

Results

172 patients were enrolled for the study (53M; 119F), mean age at diagnosis 47.2 years (range 26-78 years). Genetic analysis detected a LS (7 MLH1, 8 MSH2, 6 MSH6, 3 PMS2) in 24/172 (13.9%), a VUS (5 MLH1, 8 MSH2, 9 MSH6, 2 PMS2) in 24/172 (13.9%) cases and a negative test in 124 patients (72.1 %). Clinical features showed a colorectal cancer (CRC) in 20/24 (83.3%) LS; 14/24 (58%) VUS pts and 61/124 (49%) negative pts; an endometrial cancer in 6/20 (25%) LS; 7/14 (29%) VUS; 49/61 (39.5%) negative test pts (p. 0.007, significant at p<0.05). Multiple primary cancers were present in 11/20 LS(45.8%) ; 5/14 (20.8%) of VUS ; 23/61 (18.5%) of negative test pts. A family history of cancer fulfilling Amsterdam I or II criteria was present in 37.5% in either LS or VUS pts and in 15.3% of negative test pts.

Conclusion

Multigene testing increases the likelihood of detecting a VUS in patients with suspicion of hereditary syndromes. Because of uncertainity of its pathologenic role, oncological surveillance for target organs is undefined, guidelines are lacking and this is of particular concern for psysicians . In the present study, emerged some different clinical features between LS and MMR VUS patients: female gender was prevalent in VUS and negative test groups, a colo-rectal cancer and multiple primary cancers were significantly more represented in LS; Amsterdam criteria were predominant in LS and VUS groups. These preliminary data suggest that the VUS group has peculiar clinical features that in addition to segregation analysis and functional assays, could help to predict /support variant pathogenicity or benignity and subsequent clinical management.

References

1) Rolf H Sijmons, Marc S Greenblatt, Maurizio Genuardi. Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians Fam Cancer2013 Jun;12(2):181-7.doi: 10.1007/s10689-013-9629-8.
2) Felicia Adam, Muriel Fluri, Amina Scherz and Manuela Rabaglio. Occurrence of variants of unknown clinical significance in genetic testing for hereditary breast and ovarian cancer syndrome and Lynch syndrome: a literature review and analytical observational retrospective cohort study. BMC Medical Genomics (2023) 16:7
https://doi.org/10.1186/s12920-023-01437-7

Introduction

Lynch syndrome (LS) is a hereditary condition associated with an increased risk of early colorectal cancer (CRC), due to mutations in DNA mismatch repair (MMR) genes, accounting for 3-5% of all CRC. High-definition screening colonoscopies in specialized centers reduce CRC mortality in this setting.

Aims & Methods

We conducted a clinical audit in a large cohort of these patients, ultimately to enhance the quality of care provided. We performed a retrospective evaluation of the clinical characteristics and risk factors of LS patients under surveillance at our reference center. CRC surveillance program includes colonoscopy every 2 years, starting at ages 20–25 for MLH1/MSH2 carriers and 30–35 for MSH6/PMS2 carriers. We further analyzed compliance to surveillance protocol and its clinical outcomes – our primary endpoint was mortality rate due to CRC and secondary endpoints were time to first advanced colorectal lesion and CRC staging at diagnosis.

Results

A total of 508 patients were included (44% MSH2, 23% MLH1, 20% MSH6, and 13% PMS2). The mean age at surveillance initiation was 44.4 years, with 35.6% starting after the diagnosis of a Lynch syndrome-associated neoplasia. The mean surveillance duration was 5.6 years. Each patient underwent an average of four colonoscopies, with 50% performed within the recommended surveillance intervals.
During the follow-up period, 35 patients were diagnosed with CRC, with a mean time to first advanced colorectal polyp of 3.7 years and for the first CRC diagnosis of 4.8 years. Having any colonoscopy outside the established interval was not associated with higher CRC incidence (p = 0,647). CRC cases diagnosed prior to surveillance initiation (n=143) were more advanced (58.1% stage ≥ II) and were treated with segmental colectomy in 80% of cases. In contrast, CRC cases diagnosed during surveillance (n=48) were detected at earlier stages (64.6% Tis/T1) and managed with endoscopic resection (29%) or total colectomy (56%) (p < 0.001).
The incidence of CRC was higher in MLH1/MSH2 carriers compared to MSH6/PMS2 carriers (36% vs. 22%, p = 0.0020). The mean age at first CRC diagnosis was 45.6 years for MLH1/MSH2 carriers and 49.9 years for MSH6/PMS2 carriers (p = 0.053). The CRC-related mortality rate was 0.6% (n=3), all cases diagnosed before surveillance initiation.

Conclusion

Although adherence to the CRC surveillance program in LS patients can be optimized, our findings underscore its importance in specialized reference centers. Surveillance was associated with earlier CRC detection, less invasive therapeutic approaches, and reduced CRC-related mortality. Our results also show a lower incidence of CRC and an higher age at first CCR diagnosis in MSH6/PMS2 carriers, strengthening the personalized surveillance recommendations dependent on gene specificities.

References

Castillo-Iturra, J., Sánchez, A. and Balaguer, F. (2024) ‘Colonoscopic surveillance in Lynch Syndrome: Guidelines in perspective’, Familial Cancer [Preprint]
del Carmen, G. et al. (2023) ‘Colorectal surveillance outcomes from an institutional longitudinalcohort of Lynch syndrome carriers’, Frontiers in Oncology, 13
Kastrinos, F. et al. (2021) ‘Gene-specific variation in colorectal cancer surveillance strategies for Lynch syndrome’, Gastroenterology, 161(2)

Introduction

Lynch syndrome (LS) is the most frequent hereditary cancer syndrome, responsible for 3-5% of all colorectal cancer (CRC) cases. Patients with LS are at increased risk for metachronous CRC, influenced by the specific gene involved and the extent of prior surgical intervention¹. However, the impact of colonoscopy surveillance on metachronous CRC incidence in LS carriers has not been clearly defined.

Aims & Methods

To characterize LS carriers at risk of developing metachronous CRC based on the affected gene and the extent of prior surgery. To describe follow-up characteristics, particularly the rate of colonoscopy surveillance. To report the incidence of metachronous CRC according to surgical extent and gene mutation. To analyze potential risk factors associated with metachronous CRC development.
This retrospective multicenter study included 583 LS carriers diagnosed with CRC; 43 were excluded due to missing surgical or follow-up data, resulting in 540 patients analyzed. Patients were categorized by high-risk genes (MLH1, MSH2) or low-risk genes (MSH6, PMS2) and by surgical extent (extensive or partial colectomy). Colonoscopy surveillance was defined as at least one colonoscopy following the initial CRC diagnosis or between successive CRC events in cases of metachronous CRC. Survival analysis assessed the incidence of metachronous CRC.

Results

Among the 540 included carriers, 247 (45.7%) had MLH1 mutations, 181 (33.5%) MSH2, 80 (14.8%) MSH6, and 32 (5.9%) PMS2. Participants were grouped into four categories: high-risk/extensive colectomy (N=58), high-risk/partial colectomy (N=370), low-risk/extensive colectomy (N=9), and low-risk/partial colectomy (N=103). Age at first CRC diagnosis was significantly higher in high-risk groups compared to low-risk groups. No differences were found between groups regarding sex, tumor location, or tumor stage. Median follow-up duration was 8.6 years (IQR 4.5-14.6), with no significant differences among groups. During follow-up, 107 cases of metachronous CRC occurred. Survival analysis revealed significant differences in metachronous CRC incidence (Log-rank test: p=0.006), with 10-year incidence rates of 6.4% for high-risk/extensive colectomy, 17.9% for high-risk/partial colectomy, 0% for low-risk/extensive colectomy, and 4.8% for low-risk/partial colectomy groups. Risk factors significantly associated with metachronous CRC included high-risk gene mutations (HR 2.49, 95% CI 1.2-4.77) and initial CRC diagnosis before the year 2000 (HR 1.61, 95% CI 1.02-2.55). Colonoscopy surveillance was associated with a reduced risk of metacronous CRC (HR 0.06, 95% CI 0.04-0.09).

Table 3. Metachronous CRC risk factors

Conclusion

Individuals carrying pathogenic variants in MLH1 or MSH2 who undergo partial colectomy face a markedly increased risk of developing metachronous CRC. Nonetheless, the introduction of structured colonoscopic surveillance and optimized management strategies after the year 2000 has significantly mitigated this risk. These findings are essential for informing surgical decision-making in patients with LS and CRC, particularly when evaluating the most appropriate extent of colectomy.

References

Eikenboom EL, Moen S, Van Leerdam ME, Papageorgiou G, Doukas M, Tanis PJ, et al. Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study. The Lancet Gastroenterology & Hepatology. 2023 Dec;8(12):1106–17.

Introduction

Lynch syndrome (LS) is a heritable autosomal dominant genetic condition caused by mutations in several DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6, PMS2 and EPCAM. Affected individuals have an increased life-long risk of developing cancers especially colorectal cancer (CRC) and endometrial cancer (EC). LS accounts for approximately up to 3% of all CRC. Traditionally, diagnosis was based on clinical criteria (Amsterdam II, Bethesda and revised Bethesda), which have proven to be of limited applicability in clinical practice. In recent years tumor testing via immunohistochemistry (IHC) of all CRCs for the expression of MMR proteins has successfully integrated into clinical care. Universal screening through IHC of CRC tumor samples is cost-effective and recommended by major guidelines, which also recommend its application to endometrial cancers.

Aims & Methods

Our aim was to assess the main differences between LS families where the first individual received a genetic diagnosis after IHC on tumor sample and LS families where the first individual received a genetic diagnosis due to meeting the Amsterdam II or revised Bethesda criteria. We obtained data (year of genetic test confirmation, first tumor diagnosis, family tree) of all our single center’s LS patients who undergo surveillance in our Institute (n = 101 patients). Accordingly, we grouped patients by family and identified each family’s index case-defined as the first individual to receive a genetic diagnosis - and relatives of index cases. Therefore, we divided the cohort into two groups: families whose the index case was identified after IHC on tumor sample and families whose the index case was identified due to meeting the Amsterdam II or revised Bethesda criteria. We subsequently evaluatedwhether patients identified through IHC would have also met the revised Bethesda or Amsterdam II criteria for genetic testing.

Results

We found that index cases identified through IHC (n =16; of which 8 on CRC tissue, 7 on EC tissue and 1 on lung cancer tissue) had a mean age of 57.93 years at the time of genetic diagnosis, whereas those identified through clinical criteria (n = 20) had a mean age of 46.35 years. As for the relatives, those whose index case was identified via IHC (n = 11) had a mean age of 45.72 years, while relatives of individuals diagnosed based on clinical criteria (n= 54) had a mean age of 37.96 years. Patients carrying pathogenic variants in MSH6 and PMS2 (leading to lower penetrance and a late onset of LS related cancers) were 8 out of 16 (50 %) in the IHC group and 1 out of 20 (5 %) in the clinical criteria group. Furthermore 8 out of 16 (50%) index patients diagnosed through IHC did not meet the Amsterdam II criteria.

Conclusion

The mean age of index cases diagnosed due to clinical criteria is lower than that of cases identified through IHC, probably because of the early onset of LS related cancers in these patients and since the clinical criteria require at least one case to be diagnosed at a young age (<50 years old). In contrast, universal immunohistochemistry (IHC) screening enables the detection of all patients with mismatch repair-deficient tumors, including those diagnosed later in life and those without an evident family history of cancer or carrying pathogenic variants in genes such as MSH6 and PMS2 with a lower penetrance. Our data strengthen the important role of IHC screening for MMR proteins loss of expression both in CRC and EC to find LS families that would not be possible to identify with clinical criteria only.

Introduction

Lynch syndrome (LS) is an autosomal dominant genetic disease associated with germ-line mutations of genes involved in mismatch repair (MLH1, MSH2, MSH6 and PMS2) and the EPCAM gene. LS patients are at increased risk for colorectal cancer and other malignancies (especially endometrial, ovarian, and gastric cancer). There are few reported cases of thyroid cancer in patients suffering from LS.

Aims & Methods

To systematically investigate the presence of thyroid nodules in LS patients, to assess their cytologic classes and to explore its association with genetic features of the disease. A retrospective and descriptive analysis was conducted to include all LS patients followed at CEMAD (Centro Malattie Apparato Digerente) of Fondazione Policlinico Universitario A. Gemelli IRCCS. For each patient, characteristics of LS disease and previous history of thyroid disease were evaluated. Majority of patients underwent thyroid ultrasound (US) and nodule cytology was performed when needed. Gene mutations were reviewed for each patient with thyroid nodules and previous history of thyroid disease.

Results

A total of 139 LS patients, 52 males and 87 females, were included in the study. 103 patients (74%) underwent thyroid ultrasound examination, and 7 patients (5%) had a previous history of thyroid disease (cancer or multinodular goitre). For these two groups, mean age was 51.9 years. 29 patients (21%) did not already perform US at the time of analysis. Thyroid nodules were found in 62 patients (60%) who underwent US and 9 of them (14%) had suspicious features of malignancy inducing fine-needle aspiration biopsy. Cytologic analysis classified 7 of 9 cases (78%) as TIR2 and 2 (22%) as TIR3a. Between patients with nodular thyroid disease (single nodule, multinodular goitre and cancer), most of them (25 patients, 36% of total) were carriers of MSH6 mutation, while 22 (32%), 17 (24%) and 5 (7%) had MSH2, MLH1 and PMS2 mutations, respectively.

Conclusion

A high prevalence of thyroid nodules is found in patients with Lynch Syndrome, especially in MSH6 carrier patients. Performing at least one thyroid ultrasound examination is suggested for detection of nodular thyroid disease in LS patients. Systematic investigations are needed to estimate their prevalence, features, and risk of malignant transformation.

References

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Genetic/Familial High-Risk Assessment: Colorectal Version 2.2023 — October 30, 2023

Verrienti A, Carbone A, Sponziello M, Pecce V, Cito DS, Bruno R. Papillary thyroid carcinoma as first and isolated neoplastic disease in a Lynch syndrome family member with a germline MLH1 mutation. Endocrine. 2022 Jun;77(1):199-202. doi: 10.1007/s12020-022-03048-1. Epub 2022 Apr 12. PMID: 35415788.

Pacini F, Basolo F, Bellantone R, Boni G, Cannizzaro MA, De Palma M, Durante C, Elisei R, Fadda G, Frasoldati A, Fugazzola L, Guglielmi R, Lombardi CP, Miccoli P, Papini E, Pellegriti G, Pezzullo L, Pontecorvi A, Salvatori M, Seregni E, Vitti P. Italian consensus on diagnosis and treatment of differentiated thyroid cancer: joint statements of six Italian societies. J Endocrinol Invest. 2018 Jul;41(7):849-876. doi: 10.1007/s40618-018-0884-2. Epub 2018 May 4. PMID: 29729004.

Introduction

Lynch Syndrome (LS), the most common hereditary colorectal cancer (CRC) syndrome, is associated with increased adenoma and carcinoma risks. Colonoscopy surveillance recommendations generally consider MMR gene-specific risk but remain largely standardized in terms of surveillance intensity and frequency. However, accumulating evidence suggests that genotype-specific differences in neoplasia risk may warrant more tailored approaches.

Aims & Methods

This study evaluated trends in adenoma and CRC incidence across surveillance visits stratified by genotype among LS patients. We analyzed 318 LS patients with pathogenic variants in MLH1, MSH2, MSH6, PMS2 or EPCAM each with ≥2 surveillance colonoscopies between 2015–2025 at MD Anderson Cancer Center in Texas, USA. Individuals with prior colorectal surgery, inflammatory bowel disease, incomplete colonoscopy, or sigmoidoscopy-only exams were excluded. Adenoma (tubular, tubulovillous [TVA], SSA) and advanced neoplasia (advanced adenoma or CRC) rates were assessed over three follow-up visits. Statistical comparisons used Kruskal-Wallis and Fisher’s exact tests (α=0.05).

Results

Among 205 patients with follow-up (median age 43.4, median follow-up 1089 days), tubular adenomas (TA) were observed in 58.8%, sessile serrated adenomas (SSA) in 16.2%, and advanced neoplasia (AN) in 7.8%. Five CRCs (2.4%) were identified overall. MSH2/EPCAM carriers (n=79) had the highest neoplasia burden, with TA in 57.0%, SSA in 20.3%, and 3 of 5 CRCs. MLH1 carriers (n=50) had TA in 43.4%, SSA in 2.0%, and 2 CRCs (4.0%). PMS2 (n=37) had the lowest burden (TA 21.6%, SSA 5.4%) and no CRCs. While per-visit incidence trends were not statistically significant, total adenoma count across genotypes differed significantly (p<0.05). Additionally, TA and TVA incidence at first follow-up varied significantly by genotype (p = 0.036 and 0.037, respectively).

Table: Neoplasia Outcomes by LS Genotype (n = patients with ≥1 follow-up)

Conclusion

These findings highlight important genotype-specific differences in cumulative adenoma and CRC burden among LS carriers. While MSH2/EPCAM and MLH1 carriers exhibited the highest neoplasia rates, PMS2 carriers demonstrated consistently low lesion and cancer incidence. These results support the need for genotype-based surveillance strategies to reduce unnecessary procedures while preserving cancer prevention.

Disclosure

The authors declare that they have no conflicts of interest related to this work.