Lower Cancer Incidence in Amsterdam-I Criteria Families Without Mismatch Repair Deficiency

Lindor, Noralane M.; Rabe, Kari G.; Petersen, Gloria M.; Haile, Robert W.; Casey, Graham; Baron, John A.; Gallinger, Steve; Bapat, Bharati; Aronson, Melyssa; Hopper, John L.; Jass, Jeremy R.; LeMarchand, Loïc; Grove, John S.; Potter, John D.; Newcomb, Polly A.; Terdiman, Jonathan P.; Conrad, Peggy; Möslein, G.; Goldberg, Richard M.; Ziogas, Argyrios; Anton‐Culver, Hoda; Andrade, Mariza de; Siegmund, Kim; Thibodeau, Stephen N.; Boardman, Lisa A.; Seminara, Daniela

doi:10.1001/jama.293.16.1979

Cited by 494 publications

(345 citation statements)

References 16 publications

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“…fulfillment of the Amsterdam I/II criteria and a familial or hereditary risk of colorectal cancer, and yet differ as no MMR gene mutations or defects have been identified. 38-40 Ethical approval for the study was obtained by the Scientific and Ethics Committee of the Capital Region of Copenhagen, Denmark (HD-2007–0032 and H-17001916) and reviewed by the Data Protection Agency (AHH-2017–071). In rectal cancer, neoadjuvant radiotherapy may induce inflammation and immune cell infiltration.…”

Section: Methodsmentioning

confidence: 99%

Immunoprofiles of colorectal cancer from Lynch syndrome

et al. 2018

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Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells, loss of beta-2-microglobulin (B2M) and up-regulation of PD-L1 on tumor cells. The gene expression signature of Lynch syndrome tumors was characterized by upregulation of genes related to antigen processing and presentation, apoptosis, natural killer cell-mediated cytotoxicity, and T cell activation. Tumors with loss of B2M and up-regulation of PD-L1 showed distinctive immunogenic profiles. In summary, our data demonstrate a complex tumor-host interplay where B2M loss and PD-L1 up-regulation influence immunological pathways and clinical outcome in Lynch syndrome tumors. Immunological classification may thus aid in the preselection of colorectal cancers relevant for treatment with anti-PD-1/PD-L1 therapies.

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Section: Methodsmentioning

confidence: 99%

Immunoprofiles of colorectal cancer from Lynch syndrome

et al. 2018

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“…Once a registry decided to return genetic results to participants, they then decided which of the genetic test results (e.g., MSI, IHC, deleterious germline mutations and/or variants of uncertain significance (VUS), or Familial Colorectal Cancer Type X; Lindor et al 2005) would be returned and to which research participants (i.e., cases and/or relatives). These considerations were guided by the principle that genetic test results must have clinical utility and validity prior to disclosure in the research setting.…”

Section: Resultsmentioning

confidence: 99%

“…The five registries currently returning genetic test results all chose to return information about deleterious MMR and biallelic MutYH mutations to both cases and their relatives. However, the assessment of the utility of other research findings varied, with some registries choosing to return information about VUS findings and if a family met the criteria for Familial Colorectal Cancer Type X (Lindor et al 2005), while others decided not to offer this information to participants.…”

Section: Resultsmentioning

confidence: 99%

“…Familial Colorectal Cancer Type X refers to families that conform to the original Amsterdam I Criteria (Vasen et al 1991) but have proficient DNA MMR in the colorectal tumors, thereby distinguishing them from LS. The increased cancer risks in such families appear to be limited to CRC, and screening recommendations are based upon the family history (Lindor et al 2005). …”

Section: Setting: Colon Cancer Family Registrymentioning

confidence: 99%

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How do researchers manage genetic results in practice? The experience of the multinational Colon Cancer Family Registry

et al. 2013

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There is consensus internationally that research participants should be offered the opportunity to receive clinically relevant genetic information identified through research, but there is little empirical peer-reviewed work documenting this process. We report the experience of conducting genetic research with nearly 35,000 participants in the Colon Cancer Family Registry, based in the USA, Canada, Australia, and New Zealand. Investigators from six multinational sites provided information about disclosure protocols, implementation, and uptake of genetic results and made suggestions to inform practice. Across 5 of the 6 registry sites, 1,634 participants in families with mismatch repair or MutYH gene muta- Genet (2014) 5:99-108 DOI 10.1007 effort to return results. We offer suggestions in five key areas: (1) planning for the disclosure process, (2) participant information, (3) autonomy of participants, (4) monitoring scientific progress, and (5) involvement of stakeholders. Despite increasing discussion of the importance of returning incidental findings from genetic research, this paper highlights the considerable diversity, challenges, and costs faced in practice when returning expected findings with established utility and validity. We argue that more work is needed to ensure that genetic results in research are optimally managed.

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“…By the Lynch definition of defects in DMMR genes, this family cannot be termed true Lynch syndrome due to the lack of mutation in a DMMR gene. Families such as this one without a defined mutator phenotype have been described previously and represent an important group for molecular and clinical study (20)(21)(22). Mutations in the DMMR genes are only identified in 50-70% of families meeting stringent Amsterdam I criteria (20).…”

Section: Discussionmentioning

confidence: 96%

Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair

Case

Zighelboim

Mutch

et al. 2008

Gynecologic Oncology

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Objectives-We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication.Methods-A detailed history and review of medical records was undertaken to construct a fourgeneration pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation.Results-Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer.Conclusions-We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.

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Lower Cancer Incidence in Amsterdam-I Criteria Families Without Mismatch Repair Deficiency

Cited by 494 publications

References 16 publications

Immunoprofiles of colorectal cancer from Lynch syndrome

Immunoprofiles of colorectal cancer from Lynch syndrome

How do researchers manage genetic results in practice? The experience of the multinational Colon Cancer Family Registry

Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair

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