Clinical Criteria For Hereditary Cancer Research Articles

Prevalence of pathogenic variants in non-BRCA genes and their impact on clinical practice in Argentina.

e22534 Background: The use of NGS has made it easier and more cost-effective to analyze genes associated with hereditary cancer predisposition syndromes. Germline alterations in breast cancer (BC) have an estimated prevalence of 10.7% of Pathogenic Variant or Likely Pathogenic (P/LP), with up to 8.0% in BRCA1/2 and 2.7% in CHEK2, ATM and PALB2 genes; they increase the risk of cancer 2 to 5 times. To date, two studies of P/LP in genes non-BRCA1/2 have been conducted in Argentina with frequencies of 4.5 and 4.7% in patients with personal and/or family history of BC. Methods: We report the frequency of P/LP in non-BRCA1/2 genes in patients with hereditary cancer criteria referred to the Oncogenetics Program at Hospital Privado Universitario de Córdoba between 01/2016 and 12/2022. A retrospective analysis was conducted on patients with BC, ovarian cancer (OC), pancreatic cancer (PaC), or prostate cancer (PC) who had clinical criteria for hereditary cancer. NGS and/or Sanger methods were used to sequence the samples, and the frequency of P/LP, novel P, and their association with other variants were collected and associated with the clinical features of the index case. Results: Of 283 cases studied, 85 (30.0%) were P/LP, with 53 (18.7%) detected in BRCA1/2 and 32 (11.3%) in other genes. Among the 32 mutations found in non-BRCA1/2 genes, the frequency of P/LP was 4.59% for PALB2 and 2.47% for CHEK2, 1.06% for TP53, 0.7% for MUTHY and 0.35% each for ATM, BRIP1, FANCC, MLH1, MSH2, FANCM and PTEN. The cases studied correspond to BC (75%), PaC (9.3%) and asymptomatic patients (15.7%), two of which belonged to families with an identified mutation in PALB2, other two in CHEK2, and one with no available index case with a mutation in ATM. The age at diagnosis in the cases with personal history was 44.5 years (20-66) with a very early age in the cases with TP53 mutations and two cases with PALB2 variants. Of the total mutations in non-BRCA1/2 genes, two were found to be associated with other pathogenic mutations and 12 were associated with VUS. Within our study, four remarkable findings were identified in PALB2 gene: 1) five unrelated families share the pathogenic c.1653T > A; 2) two unrelated families share the pathogenic c.1959T > A; 3) the novel c.2872_2875del LP variant was detected and 4) the frequency of the variant c.1653T > A suggests the possibility of a founder effect. Our study shows a higher frequency of P/LP in non-BRCA genes than those reported in Argentina and Latin America, which may be due to the selection of a population with family and/or personal history of cancer. Conclusions: It is important to perform multi-gene testing including moderate-penetrance genes to determine the hereditary susceptibility to cancer in our population and to identify vulnerable groups that require more specialized surveillance than the general population. This will help individuals with a higher risk of developing cancer to take effective preventive actions.

Prospective study of germline and somatic alterations for early onset lung cancer patients (EOLUNG MASTER protocol).

TPS9122 Background: Lung cancer (LC) is a rare disease among young adults. Polymorphisms in genes involved in carcinogenic metabolism of tobacco and/or xenobiotic metabolism have been identified in those patients. The growing use of next generation sequencing (NGS) unravelled germline mutations in genes associated with hereditary cancer in patients with LC. However, germline DNA mutations have not been systematically studied in young adults with LC. Early onset LC patients are likely to harbor actionable somatic mutations. Broad hybrid NGS can identify actionable genomic alterations in LC patients deemed driver negative by routine molecular analysis. Trial Design: This is a multicentre, prospective, single-cohort study to determine whether young patients with LC harbor germline mutations and to evaluate the impact of NGS using Foundation One platform on the therapeutic options and overall survival for this specific patient population. Major inclusion criteria: 1) patients already or newly diagnosed of non-small cell lung cancer at any stage at age < 51; 2) to have sufficient tumor sample to perform standard molecular diagnosis ( EGFR/ALK/ROS1/BRAF); 3) to provide written informed consent for the study. Methods: After signing the informed consent form, family history of cancer and smoking history will be collected and a peripheral blood sample will be obtained. Germline targeted sequencing will be carried out in our centre using a customized hereditary cancer panel (I2HCP) of 136 genes designed to cover the coding exons and intron-exon boundaries of genes associated with moderate or high risk of hereditary cancer. Patients with clinical criteria for hereditary cancer or harboring pathogenic or probably pathogenic germline alteration will be referred to the genetic counselling unit. Patients will follow the usual clinical pathway for biomarker analysis and in case of remaining tumour material it will be used for conducting comprehensive genomic profiling through Foundation One platform. When tumour material available will not be sufficient to perform NGS, a tumour re-biopsy will be considered. Enrolment begun on June 2018 and, to date, a total of 41 patients have been included in the study.

Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria

The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.

A molecular analysis and clinical follow up: a strategy for hereditary cancer prevention

According to the Brazilian National Institute, the incidence of cancer in Minas Gerais state, Brazil, is approximately 50.000 new cases per year. 5–10% of these cases are associated with hereditary predisposition. This project is a partnership among the public Cancer Hospital of Divinopolis, Federal University of São João del Rei and a Non Governamental Organization against Cancer. The objective is to structure a center for familial cancer control based in clinical and molecular analysis. Patients with clinical suspected familial cancer are assisted, familial history is collected and heredograms are made in Progeny software. Risk assessment is done and families who fill clinical criteria for hereditary cancer are advised about the importance of close follow‐up. After consent, 5 ml of blood are collected for molecular studies. Specific genes related to the suspected syndrome are screened for mutations. The techniques used are High Resolution Melting (HRM) and Sequencing. From January 2011 to date, 19 families were registered for different cancer familial syndromes. At this moment, different genes have been analyzed by HRM and are being sequenced. This study will help to identify the individuals with real risk, so that genetic counseling can be done. The partnership is a promissing solution for the establishment of clinical‐molecular projects in regions with limited economic resources. Support: CNPq and FAPEMIG.