Case Report Series: Aggressive HR Deficient Colorectal Cancers Related to BRCA1 Pathogenic Germline Variants

Freire, Maria Valeria; Martin, Marie; Thissen, Romain; Marcke, Cédric Van; Segers, Karin; Sepulchre, Edith; Leroi, Natacha; Lété, Céline; Fasquelle, Corinne; Radermacher, J.; Gökburun, Yeter; Collignon, Joëlle; Sacré, Anne; Josse, Claire; Palmeira, Léonor

doi:10.3389/fonc.2022.835581

Cited by 5 publications

(5 citation statements)

References 36 publications

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“…Homologous recombination deficiency (HRD) can be assessed by the HRD score, which is a combination of homologous recombination deficiency, telomeric-allelic imbalance, and large-scale state transitions. One study reported that BRCA1 variants can be involved in CRC development through HRD and suggested that young patients with a history of microsatellite-stable colorectal cancer could be considered for BRCA1 screening (Freire et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Single‐cell dissection reveals the role of DNA damage response patterns in tumor microenvironment components contributing to colorectal cancer progression and immunotherapy

Shen

Wang

et al. 2023

Genes to Cells

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Colorectal cancer (CRC) is one of the leading malignant cancers. DNA damage response (DDR), referring to the molecular process of DNA damage, is emerging as a promising field in targeted cancer therapy. However, the engagement of DDR in the remodeling of the tumor microenvironment is rarely studied. In this study, by sequential nonnegative matrix factorization (NMF) algorithm, pseudotime analysis, cell–cell interaction analysis, and SCENIC analysis, we have shown that DDR genes demonstrate various patterns among different cell types in CRC TME (tumor microenvironment), especially in epithelial cells, cancer‐associated fibroblasts, CD8+ T cells, tumor‐associated macrophages, which enhance the intensity of intercellular communication and transcription factor activation. Furthermore, based on the newly identified DDR‐related TME signatures, cell subtypes including MNAT+CD8+T_cells‐C5, POLR2E+Mac‐C10, HMGB2+Epi‐C4, HMGB1+Mac‐C11, PER1+Mac‐C5, PER1+CD8+T_cells‐C1, POLR2A+Mac‐C1, TDG+Epi‐C5, TDG+CD8+T_cells‐C8 are determined as critical prognostic factors for CRC patients and predictors of immune checkpoint blockade (ICB) therapy efficacy in two public CRC cohorts, TCGA‐COAD and GSE39582. Our novel and systematic analysis on the level of the single‐cell analysis has revealed the unique role of DDR in remodeling CRC TME for the first time, facilitating the prediction of prognosis and guidance of personalized ICB regimens in CRC.

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Section: Discussionmentioning

confidence: 99%

Single‐cell dissection reveals the role of DNA damage response patterns in tumor microenvironment components contributing to colorectal cancer progression and immunotherapy

Shen

Wang

et al. 2023

Genes to Cells

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“…Unfortunately, due to the still relative low occurrence of such germline variants, large numbers of CRC cases, that undergo extensive multigene panel testing as well as immunohistochemical staining for all four MMR proteins, would be extremely beneficial to study this relationship. Such pathogenic germline variants in HRR genes like BRCA1 should always be considered especially in young CRC cancer patients ( 57 ). However, all our patients with MLH1 - /PMS2 - /MSH6 - cancers were over 60 years of age at time of diagnosis and did not have a familiar history suspicious for cancer predisposing syndromes.…”

Section: Discussionmentioning

confidence: 99%

Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes

et al. 2022

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Immunohistochemical analysis of mismatch repair (MMR) protein expression is widely used to identify tumors with a deficient MMR (dMMR). MMR proteins (MLH1/PMS2 and MSH2/MSH6) work as functional heterodimers, which usually leads to the loss of expression in only one functional MMR heterodimer. Recently, there have been studies showing the simultaneous loss of immunoexpression in proteins of both heterodimers. Yet, this phenomenon has been rarely investigated. In this study, we retrospectively considered cases of different digestive system cancers (gastric cancer, ampullary cancer, small bowel cancer, colorectal cancer), which were immunohistochemically tested for dMMR within a 4-year period at our university hospital (n=352). Of the 103 cases showing dMMR, 5 cases (1.4% of all, 5.1% of dMMR cases) showed a concurrent loss of MLH1, PMS2 and MSH6 immunoexpression, whereas in the other 98 dMMR cases only one MMR heterodimer was affected. MLH1-/PMS2-/MSH6- cancer cases almost arose throughout the entire digestive tract: from the gastric antrum to the left colic flexur. To provide a comprehensive molecular characterization of this MLH1-/PMS2-/MSH6- immunophenotype, tumors were analyzed for microsatellite instability, MLH1 promotor hypermethylation and BRAF exon 15 status. Furthermore, we performed next-generation sequencing focusing on genes related to DNA repair. Here, we could detect pathogenic germline variants as well as multiple sporadic mutations in different genes involved in MMR and homologous recombination repair (HRR) respectively. The affected MMR/HRR-related genes were: ATM, BARD1, BRCA1, CDK12, CHEK1, CHEK2, FANCA, MLH1, MSH6, PALB2, TP53. Considering the biologic function of HRR/MMR proteins as potential drug targets and the low frequency of most of these mutations in digestive system cancers in general, their common occurrence in our MLH1-/PMS2-/MSH6- cases seems to be even more noteworthy, highlighting the need for recognition, awareness and further investigation of this unusual IHC staining pattern.

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“…Different studies have found the presence of variants in BRCA1 and BRCA2 : in a total of 450 patients with early onset colorectal cancer, four variants were identified in BRCA1 and one variant in BRCA2 [ 44 ]; in 1260 individuals with a family history of LS, 8% had variants in these genes [ 45 ]; and in a cohort of 961 endometrial cancer patients, 1.04% presented with a PV [ 46 ]. PVs in BRCA1 and BRCA2 are classically associated with hereditary breast and ovarian cancer syndromes [ 47 ]. Colorectal cancer is not included in the BRCA1/2 tumor spectrum; published guidelines do not recommend increased detection of this type of neoplasm in carriers of mutations in these genes.…”

Section: Discussionmentioning

confidence: 99%

A Previously Unrecognized Molecular Landscape of Lynch Syndrome in the Mexican Population

Padua-Bracho

Velázquez-Aragón

Fragoso-Ontiveros

et al. 2022

IJMS

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Lynch syndrome (LS) is the main hereditary colorectal cancer syndrome. There have been few reports regarding the clinical and molecular characteristics of LS patients in Latin America; this is particularly true in the Mexican population, where no information is available. The present study aims to describe the clinical and molecular spectrum of variants in a cohort of patients diagnosed with LS in Mexico. We present a retrospective analysis of 412 patients with suspected LS, whose main site of cancer diagnosis was the colon (58.25%), followed by the endometrium (18.93%). Next-generation sequencing analysis, with an extensive multigene panel, showed that 27.1% (112/414) had a variant in one of the genes of the mismatch repair pathway (MMR); 30.4% (126/414) had a variant in non-MMR genes such as CHEK2, APC, MUTYH, BRCA1, and BRCA2; and 42.5% (176/414) had no genetic variants. Most of the variants were found in MLH1. Pathogenic variants (PVs) in MMR genes were identified in 65.7% (96/146) of the total PVs, and 34.24% (45/146) were in non-MMR genes. Molecular and clinical characterization of patients with LS in specific populations allowed personalized follow-up, with the option for targeted treatment with immune checkpoint inhibitors and the development of public health policies. Moreover, such characterization allows for family cascade testing and consequent prevention strategies.

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Case Report Series: Aggressive HR Deficient Colorectal Cancers Related to BRCA1 Pathogenic Germline Variants

Cited by 5 publications

References 36 publications

Single‐cell dissection reveals the role of DNA damage response patterns in tumor microenvironment components contributing to colorectal cancer progression and immunotherapy

Single‐cell dissection reveals the role of DNA damage response patterns in tumor microenvironment components contributing to colorectal cancer progression and immunotherapy

Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes

A Previously Unrecognized Molecular Landscape of Lynch Syndrome in the Mexican Population

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