Precancerous neoplastic cells can move through the pancreatic ductal system

Makohon-Moore, Alvin; Matsukuma, Karen; Zhang, Ming; Reiter, Johannes G.; Gerold, Jeffrey M.; Jiao, Yuchen; Sikkema, Lisa; Attiyeh, Marc A.; Yachida, Shinichi; Sandone, Corinne; Hruban, Ralph H.; Klimstra, David S.; Papadopoulos, Nickolas; Nowak, Martin A.; Kinzler, Kenneth W.; Vogelstein, Bert; Iacobuzio‐Donahue, Christine A.

doi:10.1038/s41586-018-0481-8

Cited by 96 publications

(94 citation statements)

References 45 publications

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“…Re-review of the histology of the first primary tumor and associated imaging studies did not suggest the presence of a cystic neoplasm. These findings are highly indicative of two independent primary tumors that arose from distinct precursors (38).…”

Section: Resultsmentioning

confidence: 83%

Evolutionary Origins of Recurrent Pancreatic Cancer

Sakamoto

Attiyeh

Gerold

et al. 2019

Preprint

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Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post-treatment sampling as a component of management of recurrent pancreatic cancer.

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Section: Resultsmentioning

confidence: 83%

Evolutionary Origins of Recurrent Pancreatic Cancer

Sakamoto

Attiyeh

Gerold

et al. 2019

Preprint

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“…Previous reports have suggested that intrapancreatic metastasis may serve as another evolutionary scenario for multiple PDAC . A recent study has suggested that precancerous intraepithelial neoplasms can spread contiguously or disseminate discontiguously along the pancreatic ductal system to form multifocal clonal lesions . Therefore, we hypothesized that two distinct pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to the formation of multiple PDAC.…”

Section: Introductionmentioning

confidence: 93%

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

et al. 2020

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There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co‐occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next‐generation sequencing of 50 cancer‐related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.

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“…Similarly, around 33% of humans harbor precursor lesions in their pancreas but the life-time risk of developing pancreatic cancer is 1.6% (NCI Seer 2018; Makohon-Moore and Iacobuzio-Donahue 2016). Hence, most precursor lesions do not progress to cancer within the life-time of humans (Makohon-Moore et al 2018;Lang et al 2020). Because cancer incidence strongly depends on factors such as age, genetic predisposition, life-style, or exposure to mutagens (e.g., sun, smoke, etc.…”

Section: Discussionmentioning

confidence: 99%

“…Martincorena and Campbell 2015;Yokoyama et al 2019;Makohon-Moore et al 2018), and hence DNA shed from these cells can hamper the specificity of a cancer screening test…”

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confidence: 99%

A mathematical model of ctDNA shedding predicts tumor detection size

Avanzini

Kurtz

Chabon

et al. 2020

Preprint

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Early cancer detection aims to find tumors before they progress to an uncurable stage. Prospective studies with tens of thousands of healthy participants are ongoing to determine whether asymptomatic cancers can be accurately detected by analyzing circulating tumor DNA (ctDNA) from blood samples. We developed a stochastic mathematical model of tumor evolution and ctDNA shedding to investigate the potential and the limitations of ctDNA-based cancer early detection tests. We inferred ctDNA shedding rates of early stage lung cancers and calculated that a 15 mL blood sample contains on average only 1.5 genome equivalents of ctDNA for lung tumors with 1 billion cells (size of ~1 cm 3 ). We considered two clinically different scenarios: cancer screening and cancer relapse detection. For monthly relapse testing with a sequencing panel covering 20 tumor-specific mutations, we found a median detection size of 0.24 cm 3 corresponding to a lead time of 160 days compared to imaging-based relapse detection. For annual screening, we found a median detection size of 2.8-4.8 cm 3 depending on the sequencing panel size and on the mutation frequency. The expected detection sizes correspond to lead times of 390-520 days compared to current median lung tumor sizes at diagnosis. This quantitative framework provides a mechanistic interpretation of ctDNA-based cancer detection approaches and helps to optimize cancer early detection strategies.

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Precancerous neoplastic cells can move through the pancreatic ductal system

Cited by 96 publications

References 45 publications

Evolutionary Origins of Recurrent Pancreatic Cancer

Evolutionary Origins of Recurrent Pancreatic Cancer

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

A mathematical model of ctDNA shedding predicts tumor detection size

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