Cancer Predisposition Syndrome Research Articles

A case series of non-small cell lung cancer patients with EGFR or HER2 exon 20 insertion in Li Fraumeni syndrome.

Germline pathogenic mutations in TP53 gene are associated with a cancer predisposition syndrome known as Li Fraumeni syndrome. Albeit infrequently, non-small cell lung cancer, especially as oncogene-addicted disease, may be diagnosed in young patients with Li Fraumeni syndrome. We report three cases of patients affected by Li Fraumeni syndrome who developed non-small cell lung cancer with EGFR or HER2 exon 20 insertions. The first patient suffered from liposarcoma and, then, brain metastases from HER2-mutated non-small cell lung cancer: after stereotactic radiotherapy, he benefited from enrollment in a clinical trial with a HER2-targeted therapy. The second young patient was a female with personal history of rhabdomyosarcoma, diagnosed with brain metastases from EGFR-mutated non-small cell lung cancer: enrollment in a clinical trial led to a temporary clinical benefit. The last case was a female diagnosed with breast carcinoma, ovarian granulosa cell tumor and advanced EGFR-mutated non-small cell lung cancer at a young age. Young patients affected by oncogene-addicted non-small cell lung cancer and with a positive familial cancer history should be referred for an accurate genetic counselling to look for Li Fraumeni syndrome. The underlying molecular connection between TP53 and HER family receptor tyrosine kinases remains unclear, but an extensive molecular characterization of tumors from patients with Li Fraumeni syndrome should always be performed, to offer patients a personalized therapeutic approach.

Cost-effectiveness of the McGill interactive pediatric oncogenetic guidelines in identifying Li-Fraumeni syndrome in female patients with osteosarcoma.

Li-Fraumeni syndrome (LFS) is a penetrant cancer predisposition syndrome (CPS) associated with the development of many tumor types in young people including osteosarcoma and breast cancer (BC). The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) decision-support tool provides a standardized approach to identify patients at risk of CPSs. We conducted a cost-utility analysis, from the healthcare payer perspective, to compare MIPOGG-guided, physician-guided, and universal genetic testing strategies to detect LFS in female patients diagnosed at an age of less than 18years with osteosarcoma. We developed a decision tree and discrete-event simulation model to simulate the clinical and cost outcomes of the three genetic referral strategies on a cohort of female children diagnosed with osteosarcoma, especially focused on BC as subsequent cancer. Outcomes included BC incidence, quality-adjusted life-years (QALYs), healthcare costs, and incremental cost-utility ratios (ICURs). We conducted probabilistic and scenario analyses to assess the uncertainty surrounding model parameters. Compared to the physician-guided testing, the MIPOGG-guided strategy was marginally more expensive by $105 (-$516; $743), but slightly more effective by 0.003 (-0.04; 0.045) QALYs. Compared to MIPOGG, the universal testing strategy was $1333 ($732; $1953) more costly and associated with 0.011 (-0.043; 0.064) additional QALYs. The ICUR for the MIPOGG strategy was $33,947/QALY when compared to the physician strategy; the ICUR for universal testing strategy was $118,631/QALY when compared to the MIPOGG strategy. This study provides evidence for clinical and policy decision-making on the cost-effectiveness of genetic referral strategies to identify LFS in the setting of osteosarcoma. MIPOGG-guided strategy was most likely to be cost-effective at a willingness-to-pay threshold value of $50,000/QALY.

#1193 Tracking kidney cancer initiation via somatic mutation analysis of pre-cancer cells from Von Hippel Lindau cancer predisposition syndrome

Abstract Background and Aims Somatic mutations promote the transition from a normal cell to a cancer clone. Little is known about the factors that promote mutation in normal tissues, but whole genome sequencing of pre-cancer cells, followed by mutational pattern analyses, is a revolutionary tool to understand somatic mutation mechanisms active during an individual's lifetime. In the kidney, we have shown that normal kidney tubule epithelial cells (TEC) derived from damaged PT display an excess of somatic mutations and a peculiar enrichment of mutations in exons and highly transcribed DNA compared to other cell types [1]. However, the direct contribution of this PT-specific mutational process to carcinogenesis needs further demonstration. Here, we have analyzed normal TEC that are genetically predisposed to evolve into clear cell renal cell carcinoma (ccRCC), as they harbor a germline heterozygous mutation in the tumor suppressor Von Hippel Lindau, VHL. Using this genetic model of tumor predisposition, we have tracked the PT-specific mutational process from normal cells to overt ccRCC. This study sheds light on the etiology of this mutational process, as well as its causative role in ccRCC. Method We detected somatic mutations in single genomes from normal kidney TEC from 8 control individuals and 7 VHL-disease patients in the age range 24-70. Different from our previous study [1], we isolated kidney tubule cells from the urine. Multiple TECs per individual were subjected to in vitro clonal expansion, followed by whole genome sequencing (WGS), a golden-standard method to obtain high confidence somatic mutation data. We analyzed concomitant somatic mutation- and gene expression-data from 58 clones, and expression data from 154 TEC clones. Results First, we compared our newly generated dataset (TECs obtained from urines) with our previous dataset (TECs obtained from kidney biopsies). QPCR measurements of marker gene expression and somatic mutational pattern analyses showed that the same two populations could be clonally expanded from both urines and kidney biopsies. One population expressed markers of proximal tubule (AQP1, SLC17A3) and tubule damage (VCAM1, KIM1), and showed an excess of somatic single base substitutions (SBSs). This TEC population was defined: VCAM1-PT cells. We characterized the types of SBSs that are more frequently found in VCAM1-PT genomes. The mutation spectrum was different from that induced by exposure to common mutagens, e.g. aristolochic acid, reactive oxygen species and tobacco. Normal cells, including TEC, fat and blood progenitors, showed mutation depletion in highly transcribed genes, in agreement with more efficient repair. Instead, VCAM1-PT cells showed an enrichment of specific SBS types, distinct from those induced by another transcription-coupled mutational process described in the liver. In vitro exposure of TECs to the alkylating agent ENU recapitulates some features of the spectrum of mutations observed in vivo, suggesting that VCAM1-PT cells might fail to repair damage induced by endogenous alkylating agents. The VCAM1-PT-specific mutational signature was observed in ccRCC, but not found in a variety of non-kidney cell-types and cancers. Importantly, the impact of the mutational signature was more evident in VCAM1-PT genomes from VHL-disease patients compared to similar samples from control individuals. Moreover, VCAM1-PT cells were more common (8-fold increase, chi squared test P = .026) in the urines of VHL-disease patients than in the urines of controls. Conclusion Our data show that TECs derived from damaged PTs are subjected to a specific somatic mutation process during adult life. The process is a distinctive feature of kidney cancer (ccRCC) genomes, and is more evident in patients affected by VHL-cancer predisposition syndrome. These data suggest that heterozygous loss of VHL facilitates a PT-specific, somatic mutation process involved in cancer initiation.

Uncommon molecular alterations in follicular-derived thyroid carcinoma: A single institution study

Thyroid carcinomas are the most common endocrine malignancy and commonly have alterations in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/AKT signaling pathways in well-differentiated tumors. Alternative molecular alterations driving thyroid carcinomas have been identified rarely in the literature and are more likely to occur in poorly differentiated or anaplastic cases. In this study, uncommon genetic alterations such as MLH1, MSH2, NSD3::NUTM1, RET::SPECC1L, and G3BP2::FGFR2 were identified in patients with papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, and differentiated high-grade thyroid carcinoma. Most of these tumors demonstrated an aggressive biological behavior. Atypical driver mutations in thyroid carcinomas can occur in patients with cancer predisposition syndromes as demonstrated by an NTRK1::TPM3 fusion in a patient with Li Fraumeni syndrome. In these settings of more aggressive disease, molecular testing targeting actionable fusions and mutations is important. As demonstrated in our case cohort, 100% of cases diagnosed as high-grade follicular-derived thyroid carcinoma had a mutation or fusion that is associated with worse prognosis, has a germline syndrome association requiring further work up, or an actionable mutation. This high yield seen in this cohort for molecular testing in patients with high-grade follicular-derived thyroid carcinoma suggests more routine molecular testing in this population would be a beneficial clinical practice.

O09 Microsatellite-unstable sporadic sebaceous and duodenal tumours are associated with loss of mismatch protein expression

Abstract Introduction and aims Lynch syndrome (LS) is a common heritable cancer predisposition syndrome. Tumours from patients with LS demonstrate microsatellite instability (MSI-high), a genetic signature detectable by low-cost DNA sequencing assays that is currently utilized in colorectal cancer screening. The utility of MSI assays for LS detection has not been extensively studied in unselected sebaceous skin tumours or duodenal tumours, where currently immunohistochemical (IHC) expression of mismatch repair (MMR) proteins is used. In addition, it has recently been suggested that cutaneous squamous cell carcinoma (cSCC) could be linked to LS; however MSI status has not been studied in patients with early-onset cSCC. Methods We investigated MSI status in archival formalin-fixed paraffin-embedded cases with ethical approval. We examined 110 sebaceous tumours (STs) (45 female patients, 65 male patients; median age 77 years), 50 duodenal tumours (DTs) (28 female patients, 22 male patients; median age 64 years), and 148 cSCCs selected from patients under 50 years of age (69 female patients, 79 male patients; median age 49 years). Immunohistochemistry (IHC) was performed on each MSI-high sample to determine the expression of MMR proteins MLH1, MSH2, MSH6 and PMS2. Samples that passed quality control were included in the analysis. Results A total of 42 of 106 STs (39.6%) were MSI-high. All STs had loss of at least one MMR protein. Overall, 10 of 41 (24%) DTs were MSI-high. All DTs had loss of at least one MMR protein. We found that 12 of 148 (8.1%) cSCCs were MSI-high and 5 of 12 SCCs exhibited loss of at least one MMR protein expression (41%). Conclusions MSI-high status correlated well with loss of MMR protein expression in STs and DTs samples. Future studies will help establish MSI status in tumours initially selected by MMR loss on IHC, informing its use as an adjunct to MMR IHC in LS detection in patients with STs and DTs.

Osteosarcoma Arising as a Secondary Malignancy following Treatment for Hematologic Cancer: A Report of 33 Affected Patients from the Cooperative Osteosarcoma Study Group (COSS).

Osteosarcoma may arise as a secondary cancer following leukemias or lymphomas. We intended to increase the knowledge about such rare events. We searched the Cooperative Osteosarcoma Study Group's database for individuals who developed their osteosarcoma following a previous hematological malignancy. The presentation and treatment of both malignancies was investigated, and additional neoplasms were noted. Outcomes after osteosarcoma were analyzed and potential prognostic factors were searched for. A total of 33 eligible patients were identified (male: 23, female: 10; median age: 12.9 years at diagnosis of hematological cancer; 20 lymphomas, 13 leukemias). A cancer predisposition syndrome was evident in one patient only. The hematological cancers had been treated by radiotherapy in 28 (1 unknown) and chemotherapy in 26 cases, including bone-marrow transplantation in 9. The secondary bone sarcomas (high-grade central 27, periosteal 2, extra-osseous 2, undifferentiated pleomorphic sarcoma of bone 2) arose after a median lag-time of 9.4 years, when patients were a median of 19.1 years old. Tumors were considered radiation-related in 26 cases (1 unknown). Osteosarcoma-sites were in the extremities (19), trunk (12), or head and neck (2). Metastases at diagnosis affected eight patients. Information on osteosarcoma therapy was available for 31 cases. All of these received chemotherapy. Local therapy involved surgery in 27 patients, with a good response reported for 9/18 eligible patients. Local radiotherapy was given to three patients. The median follow-up was 3.9 (0.3-12.0) years after bone tumor diagnosis. During this period, 21 patients had developed events as defined, and 15 had died, resulting in 5-year event-free and overall survival rates of 40% (standard error: 9%) and 56% (10%), respectively. There were multiple instances of additional neoplasms. Several factors were found to be of prognostic value (p < 0.05) for event-free (osteosarcoma site in the extremities) or overall (achievement of a surgical osteosarcoma-remission, receiving chemotherapy for the hematologic malignancy) survival. We were able to prove radiation therapy for hematological malignancies to be the predominant risk factor for later osteosarcomas. A resulting overrepresentation of axial and a tendency towards additional neoplasms affects prognosis. Still, selected patients may become long-term survivors with appropriate therapies, which is an argument against therapeutic negligence.

Genetic Predisposition to Sarcoma: What Should Clinicians Know?

Pathogenic germline variants in the setting of several associated cancer predisposition syndromes (CPS) may lead to the development of sarcoma. We would consider testing for a CPS in patients with a strong family history of cancer, multiple primary malignancies, and/or pediatric/adolescent/young adult patients diagnosed with other malignancies strongly associated with CPS. When a CPS is diagnosed in a patient with sarcoma, additional treatment considerations and imaging options for those patients are required. This applies particularly to the use of radiation therapy, ionizing radiation with diagnostic imaging, and the use of alkylating chemotherapy. As data and guidelines are currently lacking for many of these scenarios, we have adopted a shared decision-making process with patients and their families. If the best chance for cure in a patient with CPS requires utilization of radiation therapy or alkylating chemotherapy, we discuss the risks with the patient but do not omit these modalities. However, if there are treatment options that yield equivalent survival rates, yet avoid these modalities, we elect for those options. Considering staging imaging and post-therapy evaluation for sarcoma recurrence, we avoid surveillance techniques that utilize ionizing radiation when possible but do not completely omit them when their use is indicated.

Facial Features of Hereditary Cancer Predisposition.

In the age of telehealth medicine, an individual's facial features may provide the only physical clues signaling the presence of a heritable cancer predisposition syndrome. These syndromes include APC-associated polyposis, Birt-Hogg-Dubé syndrome, CYLD cutaneous syndrome, hereditary leiomyomatosis and renal cell cancer, multiple endocrine neoplasia, neurofibromatosis type 1, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, and tuberous sclerosis complex 1 and 2, among others. Correctly identifying characteristic features is important for genetic and nongenetic specialists as early detection can enable prompt intervention, improving patient outcomes. Advancements in the availability of genetic testing allow patients and their relatives to have more information about their genetic risk profile than before. These changes in clinical pathways, combined with improvements in screening and risk-reducing treatment, highlight the need to outline the cutaneous and morphologic features of high-risk cancer syndromes for clinicians. In this review, we describe the important facial features of hereditary cancer predisposition, with emphasis on diagnosis, cutaneous and extracutaneous manifestations, and screening.

Past, Present, and Future Therapeutic Strategies for NF-1-Associated Tumors.

Neurofibromatosis type 1 (NF-1) is a cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene that encodes the neurofibromin protein, which functions as a negative regulator of Ras signaling. We review the past, current, and future state of therapeutic strategies for tumors associated with NF-1. Therapeutic efforts for NF-1-associated tumors have centered around inhibiting Ras output, leading to the clinical success of downstream MEK inhibition for plexiform neurofibromas and low-grade gliomas. However, MEK inhibition and similar molecular monotherapy approaches that block Ras signaling do not work for all patients and show limited efficacy for more aggressive cancers such as malignant peripheral nerve sheath tumors and high-grade gliomas, motivating novel treatment approaches. We highlight the current therapeutic landscape for NF-1-associated tumors, broadly categorizing treatment into past strategies for serial Ras pathway blockade, current approaches targeting parallel oncogenic and tumor suppressor pathways, and future avenues of investigation leveraging biologic and technical innovations in immunotherapy, pharmacology, and gene delivery.

Pancreatic neuroendocrine tumors in French VHL mutation carriers: a multicentric retrospective study.

Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary cancer-predisposition syndrome caused by germline pathogenic variants (PV) in VHL gene. It is associated with a high penetrance of benign and malignant vascular tumors in multiples organs, including pancreatic neuroendocrine tumors (PanNETs), whose long-term natural history is ill-known. Patients with both documented germline PV in VHL gene and PanNETs included in the French PREDIR database between 1995 and 2022 were included. Primary endpoint was the proportion of patients with PanNET-related metastases and secondary endpoint was overall survival (OS). Genotype/phenotype correlations were studied. We included 121 patients with 259 PanNETs. Median age at diagnosis was 38 years. Median follow-up was 89.5 months. PanNET surgical resection was performed in 51 patients. Overall, 29 patients (24%) had metastases (5 synchronous, 10 metachronous), with a higher risk in case of larger PanNET size (p=0.0089; best threshold 28 mm) and grade 2 PanNET (p=0.048), and a pejorative prognostic impact (p=0.043). Patients with PV in VHL exon 1 had larger PanNETs (p=0.018), more often metastatic disease (48% vs 11.5%; p < 0.001) and a trend toward shorter OS (p=0.16). The risk of metastases associated to VHL-related PanNETs remains low (24%) but increases with tumor size >28 mm, higher grade and in case of PV located VHL exon 1. These data might help improving the management of these patients, who should be referred to an expert center.

Low-grade glioma in children with neurofibromatosis type 1: surveillance, treatment indications, management, and future directions.

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome characterized by the development of both central and peripheral nervous system tumors. Low-grade glioma (LGG) is the most prevalent central nervous system tumor occurring in children with NF1, arising most frequently within the optic pathway, followed by the brainstem. Historically, treatment of NF1-LGG has been limited to conventional cytotoxic chemotherapy and surgery. Despite treatment with chemotherapy, a subset of children with NF1-LGG fail initial therapy, have a continued decline in function, or recur. The recent development of several preclinical models has allowed for the identification of novel, molecularly targeted therapies. At present, exploration of these novel precision-based therapies is ongoing in the preclinical setting and through larger, collaborative clinical trials. Herein, we review the approach to surveillance and management of NF1-LGG in children and discuss upcoming novel therapies and treatment protocols.

Abstract PO5-08-05: Breast Cancer in PMS2 related Lynch Syndrome: evidence of a possible association?

Abstract Background: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. LS is associated with increased risk of colorectal, and endometrial cancers but breast cancer risk is uncertain, with some studies suggesting MSH6 and PMS2 PVs may have a higher risk for breast cancer. Our study outlines the incidence and clinical characteristics of breast cancer in PMS2-related LS identified at a large academic center. Methods: Patients with PMS2 PVs identified between July 2009 and May 2023 were selected from a database at the Nancy and James Grosfeld Cancer Genetic Center at Beaumont Health. Data on demographics, genetic testing, cancer types, and breast cancer characteristics were retrospectively analyzed. Results: A total of 108 patients from 74 families were found to carry a pathogenic or likely pathogenic variant in PMS2, of whom the majority were female (75%) and Caucasian (85%). The median age at genetic testing was 52y (19 to 95y). The most common variant was c.137G &amp;gt; T (p.Ser46Ile), seen in 15 of 74 (20%) families. Forty-seven patients (46%) had a personal history of cancer, with a median age at diagnosis of 58y. Of these forty-seven patients, sixteen (34%) had multiple malignancies, including one patient with six separate cancers. The most common malignancies were breast (19; 40%), colon (16; 34%), followed by uterine cancer (7), pancreas (4), and prostate (3). The median age at breast cancer diagnosis was 53y, with a range of 41-78y. The most common histopathology was invasive ductal carcinoma (54%), followed by DCIS (31%), and invasive lobular carcinoma (15%). The majority of patients had breast tumors with stage 0 or 1 (75%), grade 2 (63%), ER-positive (92%), PR positive (67%), and HER2-negative (88%). One patient had triple-negative breast cancer. Sixty-seven percent of breast cancers were less than two centimeters, and 92% were lymph node-negative. Fifty-nine percent received radiation therapy and 53% received chemotherapy. Conclusion: Our study outlines the incidence and clinical characteristics of breast cancer in PMS2-related LS. Breast cancer was the most common malignancy in our cohort of PMS2 PV carriers, accounting for 40% of all cancers, supporting a possible association between PMS2 and breast cancer. The majority of PMS2-related breast cancers were invasive ductal type, early stage, intermediate grade, and hormone receptor-positive. Further studies with larger diverse cohorts of patients with LS are needed to better characterize a possible association in order to provide tailored breast cancer screening and management guidelines for this population. Citation Format: Ujjwal Karki, Tara Rangarajan, Dana Zakalik. Breast Cancer in PMS2 related Lynch Syndrome: evidence of a possible association? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-05.

Models of care and the advanced practice nurse role in caring for children and adolescents with a cancer predisposition syndrome: a scoping review protocol.

This scoping review will examine the literature describing models of care, barriers and facilitators of care, and gaps in care delivery for children and adolescents with a cancer predisposition syndrome (CPS). It will also explore how advanced practice nurses contribute to the delivery of care for children and adolescents with a CPS. Cancer remains a leading cause of death in children and adolescents. Pediatric CPS clinics proactively aim for early diagnosis or prevention of cancer in children and adolescents with a CPS. Additionally, the holistic well-being of individuals requires a multidisciplinary team, including advanced practice nurses, to manage their complex health care needs. This review will consider both published and unpublished literature exploring aspects of models of care and the role of the nurse in pediatric CPS clinics. Literature published in English from 1991 onward will be considered. This scoping review will follow the JBI methodology for scoping reviews. The review will include searches in MEDLINE, Embase, and CINAHL Complete. Gray literature searches will be conducted in OAIster and Social Science Research Network, as well as websites of hospitals in the USA and the UK with large pediatric cancer centers. Two reviewers will screen titles, abstracts, and full-text articles. An extraction table will be used to extract relevant data from all included articles and facilitate data analysis. Results will be presented in narrative and tabular format. Open Science Framework osf.io/axkp7/.

New Paradigms in the Clinical Management of Li-Fraumeni Syndrome.

Approximately 8.5%-16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant-a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li-Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning-based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention.

Lynch Syndrome in Mexican-Mestizo families: genotype, phenotypes, and challenges in cascade testing among relatives at risk

Lynch syndrome (LS) is the most frequent cancer predisposition syndrome affecting the colon and rectum. A pathogenic variant (PV) disrupting one of the mismatch repair (MMR) genes is responsible for the disease. The spectrum of tumors in LS is heterogeneous and includes cancer of the colon and rectum (CRC), endometrium, ovaries, stomach, small bowel, urinary tract, bladder, pancreas, and skin. Knowledge of the phenotypic variation of patients with LS, the type and frequency of PVs, and cascade testing studies in the Latin American population is limited. The present study aims to recognize the PVs in MMR genes, describe the phenotype in Mexican-Mestizo patients and their relatives, and identify the acceptance rate of cascade testing of relatives at risk. We included 40 carriers of a MMR gene PV and 142 relatives that developed a LS-related neoplasm. Patients’ clinical data, number, and type of malignancies were obtained from their medical records. Amsterdam I-II, Bethesda criteria, and PREMM5® predictive model score were estimated. Available immunohistochemistry (IHC) reports were analyzed. Relatives at risk were determined from index cases pedigrees. The distribution of MMR gene mutations among 40 probands was: MLH1 (67.5%), MSH2 (22.5%), MSH6 (7.5%), and PMS2 (2.5%). Out of the 182 LS cases, 58% exhibited the LS phenotype before age 50. The most common tumor was CRC, followed by endometrial cancer in women and gastric cancer in males. We found a 90.0% concordance between the IHC and germline PV. The most frequent PV in our sample was MLH1 c.676C>T, occurring in 1/6 index cases. All probands disclosed their molecular test result to their family. Out of the 451 asymptomatic relatives at risk, 28.2% underwent germline testing. Our results highlight the importance of conducting germline genetic studies in LS since it allows the establishment of appropriate cancer screening, risk-reducing measures, and genetic cascade testing among relatives at risk. Interestingly, we observed a significantly higher prevalence of the c.676C>T variant in MLH1, probably a singular characteristic of the Mexican-Mestizo population. New strategies to facilitate accurate communication between index cases and relatives should be implemented to improve the cascade testing acceptance rate.

Living with rare genetic disease during the COVID-19 pandemic: A qualitative study of adolescents and young adults with Li-Fraumeni Syndrome

BackgroundThe COVID-19 pandemic caused large-scale shifts in healthcare access and delivery that impacted the availability of routine care such as cancer screening. Vulnerable populations, including those with rare cancer-prone genetic disease, faced considerable difficulties in managing their cancer risk. Studies characterizing the specific impacts of the pandemic on physical, mental, and emotional well-being for individuals with rare cancer-prone syndromes are emerging. This study used a patient-centered perspective to characterize how young adults with Li-Fraumeni syndrome (LFS), an inherited cancer predisposition syndrome with nearly 100% lifetime risk of cancer, managed their physical and mental health during the first year of the COVID-19 pandemic. MethodsThis exploratory, qualitative cohort study was conducted between March and July of 2021 as part of the [institution name] [study name]. Thirty adolescents and young adults (22 female, 8 male, median age 31 years, range 18-41) with a confirmed pathogenic TP53 variant completed a semi-structured qualitative interview. An interdisciplinary team conducted Thematic Content Analysis on verbatim transcribed data. ResultsMost participants (22/30, 77%) completed cancer screening during the first year of the pandemic, with a median perceived delay of 5 months (range 2-12 months) and with financial COVID-19-related burden (55%). While participants reported satisfaction with telehealth-based services, they also reported challenges establishing new provider relationships and a clear preference for in-person clinical care. Most participants reported negative or mixed impacts of COVID-19 on mental health (21/30, 70%). Social network changes were reported by 22 (73%), and almost all participants experienced negative or mixed emotions such as loss, grief, and isolation, to adaptations necessitated by COVID-19 in their social structure. ConclusionsThe COVID-19 pandemic has had detrimental effects on the physical, emotional, and social health in young adults with Li-Fraumeni, including disruptions in care. These data highlight the need for integrative strategies to be in place prior to future pandemics to prioritize and support vulnerable populations, such as those with rare disease, and to manage unforeseen large-scale shifts in healthcare access and social structure. PPIE StatementThis research team partnered with [rare disease organization(s)] that serve this community to ensure translation of findings into practice and research recommendations were guided by the principles of shared power and patient- and family-centered perspectives.

Deciphering the clinical spectrum of gastric disease in patients with Juvenile Polyposis Syndrome

Juvenile Polyposis Syndrome (JPS) is a rare hereditary autosomal dominant cancer-predisposition syndrome caused by germline pathogenic variants (PV) located in SMAD4 or BMPR1A genes. Precise clinical and endoscopic presentation as the evolution of gastric lesions remain ill-known. Clinical, endoscopic, genetic, pathological data from patients with SMAD4 or BMPR1A PVs included between 2007 and 2020 in the French network on rare digestive polyposis (RENAPOL) database were prospectively collected to address uncertainties regarding gastric involvement. Thirty-six patients were included: 25 (69.5%) had SMAD4 PVs, 11 had BMPR1A PVs. For SMAD4 PV carriers, median age at inclusion was 43.0 years [range 10-78]. At baseline esophagogastroduodenoscopy (EGD), 22/25 (88%) exhibited at least one gastric juvenile polyp, 5/25 (20%) had macroscopic signs of inflammatory gastritis. Early gastric disease was mostly located under the cardia, then progressed to gastric antrum and body. During a mean follow-up period of 55.0 months, 12/25 had gastric disease progression (i.e. new juvenile polyps (91.6%), diffuse gastric involvement (41.6%), inflammatory flat progression (25%)). Among 62 biopsies, low-grade dysplasia was observed in 5 (7.5%) samples from 2 patients. Nine carriers (36%) underwent gastrectomy (mean age of 47.2 years) due to diffuse gastric involvement or worsening clinical symptoms. Gastric adenocarcinoma (T1) was found in one gastrectomy specimen. Among the 11 patients with BMPR1A PVs, 2 had gastric hamartomatomas at baseline EGD, none with dysplasia or symptoms. Gastric involvement in JPS appears to be progressive during life, initiating in the cardia area, and mostly concerns SMAD4 PV carriers.

Strategies for diagnosis and management of CMMRD in low-resource countries: report of a Tunisian family.

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare childhood cancer predisposition syndrome, caused by biallelic pathogenic germline variants in the mismatch repair genes. Diagnosis and management of this syndrome is challenging, especially in low-resource settings. This study describes a patient diagnosed with colorectal cancer and grade 3 astrocytoma at the age of 11 and 12 respectively. Immunohistochemistry analysis showed a loss of MSH2 and MSH6 protein expression in CRC tissues of the patient. We identified by Targeted Exome Sequencing a homozygous pathogenic germline variant in exon 9 of the MSH6 gene (c.3991C > T; p.Ala1268Glyfs*6). Genetic investigation of the family showed that the father was heterozygous for the identified pathogenic variant while the brother was wild type for this variant. Our study highlights the importance of a correct and timely diagnosis of CMMRD which can have implications for treatment. It also underlines the imperative need to enhance awareness, diagnostic standards, and surveillance that are crucial for patients and their families.

Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells.

Constitutional heterozygous pathogenic variants in the exonuclease domain of POLE and POLD1, which affect the proofreading activity of thecorresponding polymerases, cause a cancer predisposition syndrome characterized by increased risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and other tumor types. The generally accepted explanation for the connection between the disruption of the proofreading activity of polymerases epsilon and delta and cancer development is through an increase in the somatic mutation rate. Here we studied an extended family with multiple members heterozygous for the pathogenic POLD1 variant c.1421T>C p.(Leu474Pro), which segregates with the polyposis and cancer phenotypes. Through the analysis of mutational patterns of patient-derived fibroblasts colonies and de novo mutations obtained by parent-offspring comparisons, we concluded that heterozygous POLD1 L474P just subtly increases the somatic and germline mutation burden. In contrast, tumors developed in individuals with a heterozygous mutation inthe exonuclease domain of POLD1, including L474P, have an extremely high mutation rate (>100 mut/Mb) associated with signature SBS10d. We solved this contradiction through the observation that tumorigenesis involves somatic inactivation of the wildtype POLD1 allele. These results imply that exonuclease deficiency of polymerase delta has a recessive effect on mutation rate.

A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency.

Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors. The highly sensitive assessment of MSI (hs-MSI) was tested on a blinded cohort of 66 blood samples and 24 CMMRD tumor samples. Hs-MSI scores were compared with low-pass genomic instability scores (LOGIC/MMRDness). The correlation of hs-MSI scores in blood with age of cancer onset and the distribution of insertion-deletion (indel) variants in microsatellites were analyzed in a series of 169 individuals (n = 68 CMMRD, n = 124 non-CMMRD). Hs-MSI achieved high accuracy in the identification of CMMRD in blood (sensitivity 98.5% and specificity 100%) and detected MSI in CMMRD-associated tumors. Hs-MSI had a strong positive correlation with whole low-pass genomic instability LOGIC scores (r = 0.89, P = 2.2e-15 in blood and r = 0.82, P = 7e-3 in tumors). Indel distribution identified PMS2 pathogenic variant (PV) carriers from other biallelic MMR gene PV carriers with an accuracy of 0.997. Higher hs-MSI scores correlated with younger age at diagnosis of the first tumor (r = -0.43, P = 0.011). Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.