Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome

ObjectiveWomen with Lynch syndrome have a risk up to 40–60% of developing endometrial cancer, which is higher than their risk of developing colorectal or ovarian cancer. To date, no data on the outcomes of patients with Lynch syndrome diagnosed with non-endometrioid endometrial cancer are available. The goal of this study was to evaluate the outcome of patients with Lynch syndrome diagnosed with non-endometrioid endometrial cancer.MethodsData from consecutive patients diagnosed with Lynch syndrome and with a histological diagnosis of non-endometrioid endometrial cancer were retrospectively collected in two referral institutes in Italy. A case–control comparison (applying a propensity matching algorithm) was performed in order to compare patients with proven Lynch syndrome and controls. Inclusion criteria were: (a) histologically-proven endometrial cancer; (b) detection of a germline pathogenic variant in one of the MMR genes; (c) adequate follow-up. Only carriers of pathogenic or likely pathogenic variants (ie, class 5 and 4 according to the InSiGHT classification) were included in the study. Survival outcomes were assessed using KaplanMeier and Cox models.ResultsOverall, 137 patients with Lynch syndrome were collected. Mean patient age was 49.2 (10.9) years. Genes involved in the Lynch syndrome included MLH1, MSH2, and MSH6 in 43%, 39%, and 18% of cases, respectively. The study population included 27 patients with non-endometrioid endometrial cancer, who were matched 1:2 with patients with sporadic cancers using a propensity matching algorithm. After a median follow-up of 134 months (range 1–295), 2 (7.4%) of the 27 patients developed recurrent disease (3 and 36 months) and subsequently died of disease (7 and 91 months). Patients diagnosed with Lynch syndrome experienced better disease-free survival (HR 7.86 (95% CI 1.79 to 34.5); p=0.006) and overall survival (HR 5.33 (95% CI 1.18 to 23.9); p=0.029) than controls.ConclusionsNon-endometrioid endometrial cancer occurring in patients with Lynch syndrome might be associated with improved oncologic outcomes compared with controls. Genetic/molecular profiling should be investigated in order to better understand the mechanism underlying the prognosis.

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Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

npj Breast Cancer ◽

10.1038/s41523-021-00279-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Na Li ◽

Belle W. X. Lim ◽

Ella R. Thompson ◽

Simone McInerny ◽

Magnus Zethoven ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Candidate Genes ◽

Familial Aggregation ◽

Loss Of Function ◽

Cancer Data ◽

Pathogenic Variants ◽

New Genes ◽

Predisposing Genes ◽

Predisposition Genes

AbstractBreast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10−9) and missense (OR 1.27, p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.

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15297 Identification of pathogenic variants in patients with melanoma who meet NCCN criteria for hereditary breast and ovarian cancer and Lynch syndrome testing

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2020.06.223 ◽

2020 ◽

Vol 83 (6) ◽

pp. AB34

Author(s):

Matthew Comeaux ◽

John Kidd ◽

Katie Larson ◽

Megan Caldwell ◽

Bradford Coffee

Keyword(s):

Ovarian Cancer ◽

Lynch Syndrome ◽

Breast And Ovarian Cancer ◽

Pathogenic Variants

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Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

Cancers ◽

10.3390/cancers13153857 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3857

Author(s):

Pilar Mur ◽

Nuria Bonifaci ◽

Anna Díez-Villanueva ◽

Elisabet Munté ◽

Maria Henar Alonso ◽

...

Keyword(s):

Colorectal Cancer ◽

Risk Score ◽

Early Onset ◽

Low Risk ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Pathogenic Variants ◽

Predisposing Genes ◽

The Mean ◽

Early Onset Colorectal Cancer

A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

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Co‐occurrence of germline pathogenic variants for different hereditary cancer syndromes in patients with Lynch syndrome

Cancer Communications ◽

10.1002/cac2.12134 ◽

2021 ◽

Vol 41 (3) ◽

pp. 218-228

Author(s):

Rosario Ferrer‐Avargues ◽

María Isabel Castillejo ◽

Estela Dámaso ◽

Virginia Díez‐Obrero ◽

Noemí Garrigos ◽

...

Keyword(s):

Lynch Syndrome ◽

Hereditary Cancer ◽

Hereditary Cancer Syndromes ◽

Pathogenic Variants ◽

Cancer Syndromes

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Multigene Panel Testing Provides a New Perspective on Lynch Syndrome

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.9260 ◽

2017 ◽

Vol 35 (22) ◽

pp. 2568-2575 ◽

Cited By ~ 68

Author(s):

Carin R. Espenschied ◽

Holly LaDuca ◽

Shuwei Li ◽

Rachel McFarland ◽

Chia-Ling Gau ◽

...

Keyword(s):

Breast Cancer ◽

Endometrial Cancer ◽

Lynch Syndrome ◽

Population Based ◽

Brca1 And Brca2 ◽

Panel Testing ◽

Multigene Panel Testing ◽

New Perspective ◽

Testing Criteria ◽

Multigene Panel

Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies. Methods We retrospectively reviewed clinical histories of patients who had multigene panel testing, including the MMR and EPCAM genes, between March 2012 and June 2015 (N = 34,981) and performed a series of statistical comparisons. Results Overall, MSH6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively. Of 528 patients who had MMR mutations, 63 (11.9%) had breast cancer only and 144 (27.3%) had CRC only. When comparing those with breast cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 × 10−5). Of the 528 patients, 22.2% met BRCA1 and BRCA2 ( BRCA1/2) testing criteria and not LS criteria, and 5.1% met neither BRCA1/2 nor LS testing criteria. MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10−7). Conclusion These results provide a new perspective on LS and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with MMR mutations.

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Abstract P6-08-02: 21-gene recurrence score results according to germline pathogenic variants inBRCA1, BRCA2, PALB2, ATM, CHEK2and Lynch Syndrome genes

10.1158/1538-7445.sabcs19-p6-08-02 ◽

2020 ◽

Author(s):

Allison W Kurian ◽

Paul Abrahamse ◽

Kevin Ward ◽

Ann S. Hamilton ◽

Dennis Deapen ◽

...

Keyword(s):

Lynch Syndrome ◽

Recurrence Score ◽

Pathogenic Variants

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EP480 The impact of gene-specific germline pathogenic variants on clinical presentation of endometrial cancer in Lynch syndrome

10.1136/ijgc-2019-esgo.539 ◽

2019 ◽

Author(s):

G Bogani ◽

V Chiappa ◽

A Ditto ◽

F Raspagliesi

Keyword(s):

Endometrial Cancer ◽

Lynch Syndrome ◽

Clinical Presentation ◽

Pathogenic Variants ◽

The Impact

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Challenges in reporting pathogenic/potentially pathogenic variants in 94 cancer predisposing genes - in pediatric patients screened with NGS panels

Scientific Reports ◽

10.1038/s41598-019-57080-9 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Adela Chirita-Emandi ◽

Nicoleta Andreescu ◽

Cristian G. Zimbru ◽

Paul Tutac ◽

Smaranda Arghirescu ◽

...

Keyword(s):

Pediatric Patients ◽

Pathogenic Variants ◽

Predisposing Genes

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Multigene Panel Testing Increases the Number of Loci Associated with Gastric Cancer Predisposition

Cancers ◽

10.3390/cancers11091340 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1340 ◽

Cited By ~ 3

Author(s):

Gianluca Tedaldi ◽

Francesca Pirini ◽

Michela Tebaldi ◽

Valentina Zampiga ◽

Ilaria Cangini ◽

...

Keyword(s):

Breast Cancer ◽

Gastric Cancer ◽

Susceptibility Genes ◽

Cancer Predisposition ◽

Panel Testing ◽

Pathogenic Variants ◽

Cancer Susceptibility Genes ◽

Number Of Patients ◽

Multigene Panel Testing ◽

Multigene Panel

The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10–50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.

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