Heterozygous mutations in DNA mismatch repair (MMR) genes result in predisposition to colorectal cancer (hereditary nonpolyposis colorectal cancer or Lynch syndrome). Patients with biallelic mutations in these genes, however, present earlier, with constitutional mismatch repair deficiency cancer syndrome (CMMRD), which is characterized by a spectrum of rare childhood malignancies and café-au-lait skin patches. The hallmark of MMR deficiency, microsatellite instability (MSI), is readily detectable in tumor DNA in Lynch syndrome, but is also present in constitutional DNA of CMMRD patients. However, detection of constitutional or germline MSI (gMSI) has hitherto relied on technically difficult assays that are not routinely applicable for clinical diagnosis. Consequently, we have developed a simple high-throughput screening methodology to detect gMSI in CMMRD patients based on the presence of stutter peaks flanking a dinucleotide repeat allele when amplified from patient blood DNA samples. Using the three different microsatellite markers, the gMSI ratio was determined in a cohort of normal individuals and 10 CMMRD patients, with biallelic germline mutations in PMS2 (seven patients), MSH2 (one patient), or MSH6 (two patients). Subjects with either PMS2 or MSH2 mutations were easily identified; however, this measure was not altered in patients with CMMRD due to MSH6 mutation.

The development of a second malignancy after diagnosis of childhood acute lymphoblastic leukemia (ALL) is a rare event. Certain second malignancies have been linked with specific elements of leukemia therapy, yet the etiology of most second neoplasms remains obscure and their optimal management strategies are unclear. This is a first comprehensive report of non-Hodgkin lymphomas (NHL) following pediatric ALL therapy, excluding stem-cell transplantation. We analyzed data of patients enrolled in 12 collaborative pediatric ALL trials between 1980-2018, who developed NHL following ALL diagnosis. Eighty-five patients developed NHL, with mature B-cell lymphoproliferations as the dominant subtype (56/85). Forty-six of these 56 cases (82%) occurred during or within six months of maintenance therapy. The majority (65%) exhibited histopathological characteristics associated with immunodeficiency, predominantly evidence of Epstein-Barr virus (EBV)-driven lymphoproliferation. We investigated 66 cases of post-ALL immunodeficiency-associated lymphoid neoplasms, 52 from our study and 14 additional cases from a literature search. With a median follow-up of 4.9 years, five-year overall survival for the 66 patients with immunodeficiency-associated lymphoid neoplasms was 67.4% (95% CI, 56-81). Five-year cumulative risks of lymphoid neoplasm- and leukemia-related mortality were 20% (95% CI, 10.2-30) and 12.4% (95% CI, 2.7- 22), respectively. Concurrent hemophagocytic lymphohistiocytosis was associated with increased mortality (HR, 7.32; 95% CI, 1.62 to 32.98; p=0.01). A large proportion of post-ALL lymphoid neoplasms are associated with an immunodeficient state, likely precipitated by ALL maintenance therapy. Awareness of this underrecognized entity and pertinent diagnostic tests are crucial for early diagnosis and optimal therapy.

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Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL)-outcomes and mutation profile from venetoclax resistant MCL patients.