Study challenges dogma about how most breast cancers occur

Science Editorial, May 30 (EFE). – Genetic inheritance influences the type of breast cancer and its prognosis, according to a Stanford Medicine study that analyzes thousands of tumors and challenges the dogma that most of these cancers arise from random mutations. which accumulate throughout life.

For the first time, it has been confirmed that genetic sequences inherited from parents – so-called germline genomes – are “actively involved” in immunosurveillance and in the types of somatic or sporadic (non-hereditary) mutations that can contribute to cancer.

That is, they influence whether cells carrying potentially cancerous mutations are recognized and destroyed by the immune system or remain undetected and develop into nascent cancer.

The findings, which could help better predict and combat breast tumors, are published in the journal Science in a paper that describes a new class of biomarkers for predicting tumor progression and a “whole new” way of understanding the origins of these cancers.

With the exception of a few “highly penetrating” genes that confer significant cancer risk, the role of hereditary factors remains poorly understood, and most cancers are thought to arise from random errors during cell division or from bad luck, said Christina Curtis, study author. work (only 5-10% of breast cancer cases are considered hereditary).

“This would mean that the occurrence of the tumor is random, but that is not what we observed. In contrast, we found that the path of tumor development is limited by hereditary factors and immunity,” he adds in a statement from the Stanford Institute of Medicine. (USA).

Curtis explains that his team had already postulated in 2015 that some tumors are “born bad,” meaning that their malignant and even metastatic potential is determined early in the disease, but these discoveries shed “entirely new light.” ‘ about how early this happens.

Options that move threads

Currently, only a few high-profile genetic mutations associated with cancer are used to predict cancer.

These are the BRCA1 and BRCA2 genes, which occur in one in every 500 women and are associated with an increased risk of breast or ovarian cancer, as well as rarer mutations in the TP53 gene, which causes Li Fraumeni syndrome, which predisposes to childhood and adult tumors. .

New discoveries show that there are dozens or hundreds of additional genetic variants found in healthy people that pull the strings that determine why some people remain cancer-free throughout their lives and others do not.

The researchers studied nearly 6,000 breast tumors at different stages of disease to see whether each tumor’s subtype correlated with patients’ germline oncogenic sequences.

“We wanted to understand how genetic DNA might influence tumor evolution,” explains Kathleen Hoolahan, another of the authors.

Among other things, they found that in the initial, preinvasive phase, a large number of epitopes—the part of the molecule that would be recognized by the antibody—protect against cancer, Houlahan said.

But once they have to fight the immune system and develop mechanisms to overcome it, tumors with high levels of germline epitopes become more aggressive and prone to metastasize. The picture, he concludes, changes as the tumor progresses.

“There is essentially a tug-of-war between the tumor and the immune cells,” says Curtis: “In a preinvasive setting, the emerging tumor may initially be more susceptible to immune surveillance and destruction.” “In fact, many tumors are likely to be removed this way and go undetected.”

However, “the immune system doesn’t always win” and some tumor cells may not be destroyed.

Ramon Salazar, head of the department of medical oncology and director general of the Catalan Institute of Oncology, believes that this study, in which he is not involved, is “of excellent quality and very innovative” because the hypothesis demonstrated breaks the paradigm.

For the first time, inherited genetic composition has been found to influence immunosurveillance and the types of somatic or sporadic mutations that can contribute to cancer, he told the Scientific Media Center of Spain, a science resource platform for journalists. .

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