Suspected Hereditary Cancer Syndromes in Young Patients: Heterogeneous Clinical and Genetic Presentation of Colorectal Cancers

Abstract

Colorectal cancer (CRC) is rare in young patients without a confirmed family history of cancer. Reports of an increased prevalence of POLD1/POLE mutations in young patients with colorectal cancer have raised awareness and support routine genetic testing for patients with early-onset tumors. In cases of CRC without proven MMR-germline mutation, molecular analyses are warranted to confirm or rule out other familial CRC syndromes. This article describes the cases of two young male patients, who presented with locally advanced and metastatic CRC, and reports the results of the germline mutational analyses done for both patients. These cases demonstrate the importance of special care and molecular diagnostic procedures for young patients with CRC. KEY POINTS: Patients with colorectal cancer who are younger than 50 years at initial diagnosis (early onset) should routinely undergo genetic testing.Early- and very-early-onset patients (younger than 40 years) with absence of microsatellite instability should be considered for tumor mutation burden testing and/or DNA polymerase proofreading mutation.The mutational signature of HSP110 within mismatch repair deficiency-related tumors may help to identify patients likely to benefit from 5-fluorouracil-based chemotherapy.Intensified, maintained, and specific surveillance may help to reduce secondary tumor progression.

Figure 1.

Immune‐based and molecular pathological analyses. (A): Flow cytometric phenotyping for assessment of immune status from patient #1 before (after first surgery), during chemotherapy, and after second surgical intervention in comparison with healthy control. (B): IFN‐γ ELISpot. Peripheral blood mononuclear cells were seeded in anti‐IFN‐γ enzyme‐linked immunospot (ELISpot) plates and cultured overnight in the presence of different microsatellite instability (MSI)‐derived peptides [27]. Finally, bound antibody was visualized by BCIP/NBT; spots were counted using an ELISpot reader. Presented are the numbers of IFN‐γ‐secreting cells per 100,000 effector cells corrected for background levels counted in the absence of target cells. (C): MSI analysis of HSP110 was done by polymerase chain reaction (PCR) amplification of target sequence using HSP110‐specific primer sequences spanning T₁₇ repeat. Fluorescently labeled DNA fragments were analyzed on an ABI 3500 Genetic Analyzer. Normal adjacent tissue from patients served as controls. Instability was scored if novel peaks were obtained compared with controls or if the ratio of peak areas of corresponding peaks in tumor samples and stable controls revealed values ≤ 0.5 or ≥ 2. (D): Mutational analysis of the POLE gene (exons 9–14) was done by PCR amplification of the target exons and subsequently analyzed by Sanger sequencing on an ABI 3500 Genetic Analyzer. Abbreviations: Ctrl, healthy control; CTX, chemotherapy; IFN‐γ, interferon γ.

Figure 2.

Molecular mechanisms of hypermutation and its applicability as a genomic biomarker for therapy decision. Depending on the germline mutation and additional somatic mutations, immunotherapeutic concepts aim to restore (e.g., in the case of POLE mutations) or reactivate (e.g., in the case of mismatch repair deficiency) preformed (T‐cell‐) mediated immune responses to control tumor disease and eventually prevent or delay relapse. Abbreviations: MHC, major histocompatibility complex; MMR, mismatch repair; PD‐1, programmed cell death 1; PD‐L1, programmed cell death ligand 1; TCR, T‐cell receptor.

Figure 3.

Strategies to diagnose hereditary cancer syndromes based on current clinical practice. A proposed algorithm for diagnostic procedures is displayed along with intensified and maintained surveillance for risk stratification of each individual patient. Abbreviations: CRC, colorectal cancer; FAP, familial adenomatous polyposis; IHC, immunohistochemistry; LS, Lynch syndrome; MAP, MUTYH‐associated polyposis; MMR‐D, mismatch repair deficiency; MMR‐P, mismatch repair proficiency; POL, DNA polymerase.