Pancreatic ductal adenocarcinoma (PDA) harbors an exceedingly poor prognosis, and is generally considered a therapy-recalcitrant disease due to poor response to conventional chemotherapy coupled with non-actionable genetic drivers (e.g. KRAS mutations). However, PDA frequently loses p16ink4a, thereby leading to deregulation of CDK4/6. Surprisingly, in established cell models and xenografts, CDK4/6 inhibition has a modest effect on proliferation and resistance develops rapidly. To determine if such weak response was an intrinsic feature of PDA, we developed primary tumor explants that maintain the tumor environment and recapitulate feuture of primary PDA. The CDK4/6 inhibitor PD-0332991 was highly efficient at suppressing proliferation in 14 of the 15 explants. In the single resistant explant, we identified the rare loss of the RB tumor suppressor as the basis for resistance. Patient-derived xenografts (PDXs) were developed in parallel, and unlike the xenografts emerging from established cell lines, the PDXs maintained the histoarchitecture of the primary tumor. These PDXs were highly sensitive to CDK4/6 inhibition, yielding a complete suppression of PDA proliferation. Together, these data indicate that primary PDA is sensitive to CDK4/6 inhibition, that specific biomarkers can delineate intrinsic resistance, and that established cell line models may not represent an adequate means for evaluating therapeutic sensitivities.

Triple-negative breast cancer (TNBC) is an uncommon but aggressive subtype of breast cancer. Obesity has been associated with an increased risk of breast cancer and worse prognosis. Some studies suggest that obese patients are less likely to achieve pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) and experience worse overall survival. Ki-67 is a proliferation marker that correlates with tumor aggressiveness. The goal of this study was to examine the impact of weight change during NCT for TNBC on pathologic response and Ki-67 reduction. Retrospective review identified 173 TNBC patients treated between 2004 and 2011. Data were collected on patient demographics, pre- and post-NCT body mass index (BMI), Ki-67, and pCR. Data analysis was performed using the two-tailed Student's t-test, analysis of variance (ANOVA), and Fisher's exact test. Sixty-six patients met final study criteria. Forty-three patients lost weight during chemotherapy and 23 gained weight. Patients in the weight gain group were significantly younger (P = 0.0013). There was no significant difference between the two groups in terms of Ki-67 reduction (P = 0.98) or pCR (P = 0.58). When patients were separated into normal weight (BMI<25 kg/m2), overweight (BMI ≥ 25 and <30 kg/m2), and obese (BMI ≥ 30 kg/m2), there was no significant difference in Ki-67 among those groups either before or after NCT. The degree of obesity did not have a significant impact on Ki-67 reduction. Weight change during NCT does not appear to correlate with Ki-67 change or achieving pCR in TNBC. This may reflect the nature of this subtype of breast cancer that is less responsive to the hormonal effects that adipose tissue exerts on cancer cell proliferation.

Phenotypic features of KBG syndrome include craniofacial anomalies, short stature, cognitive disability and behavioral findings. The syndrome is caused by heterozygous pathogenic single nucleotide variants and indels in ANKRD11, or a heterozygous deletion of 16q24.3 that includes ANKRD11. We performed genome sequencing on a patient with clinical manifestations of KBG syndrome including distinct craniofacial features as well as a history of mild intellectual disability and attention‐deficit hyperactivity disorder. This led to the identification of a 43 kb intragenic deletion of ANKRD11 affecting the first noncoding exon while leaving the coding regions intact. Review of the literature shows that this is the smallest 5′ deletion affecting only the noncoding exons of ANKRD11. Real‐time polymerase chain reaction demonstrated that the copy number variant was not present in either of the proband's parents, suggesting it occurred de novo. RNA expression analysis demonstrated significantly decreased transcript abundance compared to controls. This provides new evidence for haploinsufficiency as a mechanism of disease in KBG syndrome.

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4‐year‐old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease‐causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4‐associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

531 Background: Colorectal cancer surgery is associated with significant postoperative morbidity, which may have long-term implications on patient outcomes. We hypothesize that operative complications following surgery for colorectal cancer are associated with increased recurrence and worse survival. Methods: Using a prospectively maintained database, we reviewed patients with colorectal cancer that underwent a curative resection from 2008 to 2015. Patients were categorized by presence of any complication within 90 days from surgery and by type of complication, infectious and non-infectious. We compared clinical, pathological, and perioperative data using t-test, chi-squared test, and ANOVA. We compared overall (OS) and recurrence free survival (RFS) using Kaplan Meier and log-rank test. Multivariable Cox regression was used to compare mortality and recurrence. Results: Two hundred and twenty-nine patients underwent 104 colon and 125 rectal cancer resections (20 pelvic exenterations, 83 low anterior and 17 abdominoperineal resections) were followed for a median of 23 months. Fifty percent were completed minimally invasively. Postoperative complications occurred in 52%; 19% had a major complication (Clavien-Dindo 3-4). Postoperative complications were more likely to occur in open (61% vs. 38%, p < 0.01) and rectal operations (63% vs. 42%, p = 0.02). On multivariable analysis, OS and RFS were not statistically different in patients with complications. Patients with infectious complications had worse 3-year survival when compared to patients with non-infectious complications and without complications (58%,69%,76%, p = 0.04). Recurrence at 3 years was also significantly different among the three groups (p = 0.03). Infectious complications remained associated with worse overall survival (HR 1.8; 95% CI 1.02,3.26) and recurrence free survival (HR 1.9; 95% CI 1.06,3.39) after adjusting for patient, tumor, and perioperative data. Conclusions: Infectious complications following colorectal cancer surgery are associated with worse OS and RFS independent of tumor stage, type of surgery, and technique. Current research is ongoing to explore possible etiologies of this association.

No abstract

Heterozygous, loss-of-function germline variants in ATM have been associated with an increased lifetime risk of breast, pancreas, prostate, stomach, ovarian, colorectal, and melanoma cancers. We conducted a retrospective review of thirty-one unrelated patients found to be heterozygous for a germline pathogenic variant in ATM and identified a significant proportion of patients in this cohort with cancers not currently associated with the ATM hereditary cancer syndrome, including carcinomas of the gallbladder, uterus, duodenum, kidney, and lung as well as a vascular sarcoma. A comprehensive review of the literature found 25 relevant studies where 171 individuals with a germline deleterious ATM variant have been diagnosed with the same or similar cancers. The combined data from these studies were then used to estimate the prevalence of germline ATM pathogenic variants in these cancers, which ranged between 0.45% and 2.2%. Analysis of tumor sequencing performed in large cohorts demonstrated that the frequency of deleterious somatic ATM alterations in these atypical cancers equaled or exceeded the alteration frequency in breast cancer and occurred at a significantly higher rate than in other DNA-damage response tumor suppressors, namely BRCA1 and CHEK2. Furthermore, multi-gene analysis of somatic alterations in these atypical cancers demonstrated significant co-occurrence of pathogenic alterations in ATM with BRCA1 and CHEK2, while there was significant mutual exclusivity between pathogenic alterations in ATM and TP53. This indicates that germline ATM pathogenic variants may play a role in cancer initiation and progression in these atypical ATM malignancies, potentially influencing these cancers to be driven toward DNA-damage repair deficiency and away from loss of TP53. As such, these findings provide evidence for broadening of the ATM-cancer susceptibility syndrome phenotype to improve the recognition of affected patients and provide more efficacious, germline-directed therapies.

Neurodegenerative disorders and leukodystrophies are progressive neurologic conditions that can occur following the disruption of intricately coordinated patterns of gene expression. Exome sequencing has been adopted as an effective diagnostic tool for determining the underlying genetic etiology of Mendelian neurologic disorders, however genome sequencing offer advantages in its ability to identify and characterize copy number, structural, and sequence variants in noncoding regions. Genome sequencing from peripheral leukocytes was performed on two patients with progressive neurologic disease of unknown etiology following negative genetic investigations including exome sequencing. RNA sequencing from peripheral blood was performed to determine gene expression patterns in one of the patients. Potential causative variants were matched to the patients’ clinical presentation. The first proband was found to be heterozygous for a likely pathogenic missense variant in PLA2G6 (c.386T>C; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6 (c.2035‐926G>A). RNA sequencing indicated this latter variant created a splice acceptor site leading to the incorporation of a pseudo‐exon introducing a premature termination codon. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. Previous reports of copy number variants spanning this region of cis‐acting regulatory elements corroborated its pathogenicity. When combined with clinical presentations, these findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult‐onset demyelinating leukodystrophy, respectively. In patients with progressive neurologic disease of unknown etiology, genome sequencing with the addition of RNA analysis where appropriate should be considered for the identification of causative noncoding pathogenic variants.