Genetic analysis of subsequent second primary malignant neoplasms in long-term pancreatic cancer survivors suggests new potential hereditary genetic alterations

Abstract

BackgroundThe principal aim of this report was to study second primary malignant neoplasms (SMNs) in long-term survivors of pancreatic ductal adenocarcinoma (PDAC) with regard to the germline genetic background.Patients and methodsA total of 118 PDAC patients after a curative-intent surgery who were treated between 2006 and 2011 were analyzed. Of the 22 patients surviving for >5 years, six went on to develop SMNs. A genetic analysis of 219 hereditary cancer-predisposition and candidate genes was performed by targeted next-generation sequencing in germline DNA from 20 of these patients.ResultsOf all the radically resected PDAC patients, six patients went on to subsequently develop SMNs, which accounted for 27% of the long-term survivors. The median time to diagnosis of SMNs, which included two cases of rectal cancer, and one case each of prostate cancer, malignant melanoma, breast cancer, and urinary bladder cancer, was 52.5 months. At the time of analysis, none of these patients had died as a result of PDAC progression. We identified four carriers of germline pathogenic mutations in 20 analyzed long-term survivors. One carrier of the CHEK2 mutation was found among four analyzed patients who developed SMNs. Of the remaining 16 long-term PDAC survivors, 3 patients (19%) carried germline mutation(s) in the MLH1+ ATM, CHEK2, and RAD51D gene, respectively.ConclusionThis retrospective analysis indicates that SMNs in PDAC survivors are an important clinical problem and may be more common than has been acknowledged to be the case. In patients with good performance status, surgical therapy should be considered, as the SMNs often have a favorable prognosis.

Improvement of the Diagnosis of Isoattenuating Pancreatic Carcinomas by Defining Their Characteristics on Contrast Enhanced Computed Tomography and Endosonography with Fine-Needle Aspiration (EUS-FNA)

“…We also found in our study that patients with isoattenuating pancreatic carcinomas were operated on almost twice as often as patients with hypoattenuating pancreatic carcinomas (44.7% vs. 85.7% of patients; p = 0.001). Thus, we indirectly confirmed the fact that patients with isoattenuating pancreatic carcinoma have a better prognosis than patients with hypoattenuating pancreatic carcinoma, because surgical treatment of pancreatic carcinomas represents the only potential hope for curing patients with these carcinomas [2,21]. Our study correlates with the study of Kim et al, where almost 86% (30 of 35) of patients with isoattenuating pancreatic carcinoma were surgically resected [8].…”

“…In 2018, 458,918 new cases of pancreatic cancer, and up to 432,242 new deaths, were reported worldwide [ 1 ]. Among radically operated patients with pancreatic carcinoma, the five-year survival rate is only 4–34%, with a median survival of 17–27 months [ 2 ].…”

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

“…An increased risk has been documented in patients with melanoma [ 242 ], endometrial [ 243 , 244 ], or testicular cancer [ 245 ]. An association with pancreatic cancer is less evident [ 20 , 246 , 247 , 248 , 249 ], but mutations in genes coding for DDR proteins (including CHEK2 ) in pancreatic cancer patients were associated with improved survival [ 250 , 251 , 252 , 253 ]. Germline CHEK2 variants were shown to protect against lung cancer, including in patients with a tobacco-related disease [ 134 , 254 ].…”

Understanding the Genetic Landscape of Pancreatic Ductal Adenocarcinoma to Support Personalized Medicine: A Systematic Review

“…Among these, 527 studies were excluded for different reasons (articles not in English, PDAC patients without PVs/LPVs in the selected genes, patients carrying only somatic alterations in PDAC susceptibility genes), and 150 studies were excluded because the evaluated patients had endocrine pancreatic cancer. As a result, 169 published studies fulfilled the inclusion criteria [ 11 , 15 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 …”